Borrelia burgdorferi and Lyme Disease Detection: Difference between revisions

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Overview

Figure 1- Borrelia burgdorferi bacteria under a scanning electron micrograph. Image taken by Claudia Molins at the CDC, 2011. http://phil.cdc.gov/phil/details.asp?pid=13176.

By Roya Best

Borrelia burgdorferi is a bacterial eubacterial phylum spirochaete and a tick borne parasite.^[1] It is one of the known causative agents for Lyme Disease.^[1] Borrelia burgdorferi was named after Willy Burgdorfer who first isolated the bacteria in 1982.^[2] The spirochete is a flat wave shape that is commonly 0.3 micrometers in width and ranges from 5 to 20 micrometers in length.^[3] It has both an outer and inner membrane with a thin layer of peptidoglycan separating the membranes^[3] Seven to eleven bundled periplasmic flagella reside within the membranes and allow the bacterium to move through a highly viscosity medium, which increases its virulence factor.^[4] The flagellar filaments wrap around the cell and rotate in order to help the flagellar motor propel the bacteria in a signature corkscrew motion.^[3] The doubling time of the bacteria ranges from 24 to 48 hours.^[5] Borrelia burgdorferi is different from common pathogenic bacteria because it lacks the common virulence factors like toxins, a specialized secretion system, and lipopolysaccharides.^[1] The bacteria lacks common biosynthetic abilities and heavily relies on its host for nutrients and other factors for its survival.^[1]

Genetics

Figure 2- Chromosome and plasmid lengths and shape demonstrated. The main chromosome of Borrelia burgdorferi is linear, while the plasmids of Borrelia burgdorferi are both linear and circular. Reprinted from Glöckner G, Lehmann R, Romualdi A, Pradella S, Schulte-Spechtel U, Schilhabel M, et al. Comparative analysis of the Borrelia garinii genome. Nucleic acids research. 2004;32: 6038–46. doi:10.1093/nar/gkh953

The genome of Borrelia burgdorferi is a linear chromosome with many smaller plasmids that are both linear and circular.^[1] The linear chromosome is about 950 kb and the linear and circular plasmids range from 9 to 62 kb, which all encode 853 genes.^[1]^[6] The genome of Borrelia burgdorferi was the third ever genome sequenced.^[6] Linear chromosomes are not common in bacteria, however, in Borrelia burgdorferi it seems to provide an advantage that has continued to allow the linear chromosome to persist.^[1] The Borrelia burgdorferi genetic sequence shows that the flagella are hidden between the two membranes compared to other organisms that have it externally radiating outward.^[1] The flagella are strategically positioned in order to provide Borrelia burgdorferi an advantage in hiding from the host immune system, as this is critical in its survival.^[1]

Borrelia burgdorferi lacks the classic genes to synthesize amino acids, fatty acids, enzyme cofactors, and nucleotides.^[1] It takes advantage of its host and obtains these important materials.^[1] The inability to synthesize these things is likely lost in coevolution with ticks and other hosts.^[7] Additionally, Borrelia burgdorferi lacks the genes to use the citric acid cycle, oxidative phosphorylation, and cellular biosynthesis.^[7]^[8] Borrelia burgdorferi, however, has the genes for and derives its energy from glycolysis and fermentation of sugars.^[7]

Borrelia burgdorferi interacts with platelets, endothelial cells, chondrocytes, and extracellular matrix when infecting a host.^[6] These interactions inhibit the proper function of various mechanisms in these infected areas. This leads to the symptoms of Lyme Disease.^[6]

Lyme Disease History and Overview

Lyme Disease is an enzootic vector-borne disease that is transmitted by Ixodes ticks.^[8] Lyme Disease was first discovered by Doctor Alan Steere in 1977 when he noticed that people were being infected with an unknown pathogen in the same geographic location during the same time of the year presenting with the same symptoms.^[1] The first confirmed case was in Lyme, Connecticut, thus providing the name of the Disease.^[6] In 1981 it was finally discovered that Borrelia genus bacteria were the causative agents of Lyme Disease.^[6]

There are a few Borrelia species that can cause Lyme Disease, however, Borrelia burgdorferi is the most common in the US.^[1] Lyme Disease is the leading vector-borne disease in the US.^[1] There are an estimated 476,000 cases each year of Lyme Disease in the US according to numbers from 2010 to 2018.^[9] However, this is most likely an underestimate because Lyme Disease is difficult to diagnose.^[9] Lyme Disease is endemic to the US, Europe, and Asia.^[8] Most cases are reported during the Spring and Summer months due to the life cycle of the reservoir, the Ixodes ticks.^[1]^[8] Common animals that can become infected with Borrelia burgdorferi are white-footed mice, chipmunks, dogs, white-tailed deer, squirrels, horses, opossums, and raccoons.^[8]

Research surrounding Lyme Disease is sparse due to the lack of federal funding. The annual NIH investment in research is much lower than in other infectious diseases.^[9] Thirty million dollars a year is allocated to Lyme Disease research which affects over 470,000 individuals annually.^[9] However, 36 million dollars is allocated to West Nile Virus which only affects about 3,000 individuals and 202 million dollars is allocated to Malaria which only affects under 2,000 individuals.^[9] The lack of funding surrounding Lyme Disease is highly controversial and why individuals with the disease commonly suffer due to improper diagnosis and must tolerate its symptoms.^[9]

Transmission

Ticks become infected with Borrelia burgdorferi when they have a blood meal from an infected reservoir, such as a white-footed mouse or chipmunk.^[1] When an infected tick bites an animal or human, Borrelia burgdorferi will migrate from the tick’s midgut to the salivary glands and then into the bloodstream of the new host.^[1] The spirochete then travels from the bloodstream to various tissues within the new host.^[1] The location in which Borrelia burgdorferi lands is where the most symptoms will be experienced.^[1] While no virulence factors are found within Borrelia burgdorferi, symptoms will occur as a result of the inflammatory response and damage the bacteria causes when it replicates.^[1] Ticks can attach to any part of the animal or human in order to take a blood meal and infect the individual with Borrelia burgdorferi.^[10] However, on humans, ticks particularly like to attach to hard-to-see places.^[10] These areas include behind the near, on the scalp, armpits, and behind the knees.^[10]

Acquiring the disease depends on many factors, including, density, distribution, and prevalence of infected ticks in the individual's area.^[8] Cases of Lyme Disease are the most common in the Northeast and Northern Central states within the US.^[8] The most reported cases occur May through August due to the life cycle of ticks, tick feeding time, and increase in human activity outdoors.^[8] A tick must be attached to its new host for over 36 hours in order to transmit the disease.^[8] Adult ticks and nymph ticks can transmit the disease.^[8] However, it is much more likely to be infected by a nymph tick because of its small size and the likelihood of remaining attached for over 36 hours.^[8]

Life Cycle

Figure 3- Life cycle of Borrelia burgdorferi and Ixodes ticks. Larval ticks become infected with Borrelia burgdorferi, molt into nymphs, bite an uninfected host, and transmit Borrelia burgdorferi, leading to Lyme Disease. Reprinted from Kurokawa C, Lynn GE, Pedra JHF, Pal U, Narasimhan S, Fikrig E. Interactions between Borrelia burgdorferi and ticks. Nat Rev Microbiol. 2020;18: 587–600. doi:10.1038/s41579-020-0400-5

Tick life cycle

Ticks are the only known natural agents that can infect animals and humans with Borrelia burgdorferi.^[1] The tick genus Ixodes can become infected with and transmit Borrelia burgdorferi between hosts and reservoirs.^[1]

The life cycle of the Ixodes ticks heavily influences the transmission of Borrelia burgdorferi between various animals and humans.^[1] The tick has a life span of two years and undergoes different life stages.^[1] The egg phase of ticks has no influence on Lyme Disease and Borrelia burgdorferi can not be contracted during this stage.^[8] The larva stage is when ticks must take a blood meal to survive and grow, thus feeding on small animals, usually mice.^[8] This stage is critical to Lyme Disease as ticks can become infected with Borrelia burgdorferi.^[8] The combination of taking a blood meal and feeding upon white-footed mice is key because white-footed mice are known as one of the main reservoirs for which ticks become infected with Borrelia burgdorferi.^[8] The next stage of a tick’s life cycle is the nymph stage.^[8] At this stage, ticks can infect others with Borrelia burgdorferi.^[8] At the nymph stage, ticks also can infect small animals and humans.^[8] Nymphs are extremely small in size and can evade detection by humans, thus being attached long enough to infect humans with Borrelia burgdorferi.^[8] Ticks during the nymph stage feed in the spring and summer, when Lyme Disease cases are reported the highest.^[8] After the nymph stage, ticks molt into adults.^[8] Adult ticks can infect other animals and humans with Borrelia burgdorferi.^[8] However, it is not common for adult ticks to transmit Borrelia burgdorferi to humans because of their large size, which allows them to be easily seen and removed.^[8]

Lyme Disease life cycle

Lyme disease itself goes through a life cycle during the transmission of Borrelia burgdorferi between hosts and reservoirs.^[7] Larva or nymphs acquire Borrelia burgdorferi during their first blood meal from an infected host.^[7] Once infected, Borrelia burgdorferi persists in the tick’s midgut.^[7] When the infected nymph bites an uninfected animal the bite triggers the Borrelia burgdorferi to replicate, escape from the tick’s midgut, and exit through the salivary glands of the tick to another host.^[7] This life cycle of Borrelia burgdorferi and Lyme Disease thus completes the enzootic cycle.^[7]

Stages and Symptoms

Figure 4- An example of the "Bull's Eye" rash that appears in 70% of those infected with Borrelia burgdorferi https://www.cdc.gov/lyme/signs_symptoms/index.html

There are three stages of Lyme Disease: early localized stage, early disseminated stage, and late disseminated stage.^[11] With each stage, new symptoms develop, and old ones may persist or disappear.^[11]

Stage 1- Early Localized Stage

Early localized Lyme Disease occurs three days to one month after the initial tick bite.^[11] The local area of the bite will be the area that experiences the most symptoms.^[11] About 70% of individuals will develop a “bull’s eye” rash.^[11]^[8] This rash is characteristic of Lyme Disease and commonly leads to diagnosis.^[11]^[8] It may get as large as 15 cm and last up to three weeks if untreated.^[11]^[12] Symptoms at this stage include flu-like symptoms, such as fever, eye redness, neck stiffness, and headaches.^[11]^[12] Antibiotics at this stage are the most effective and can prevent further growth of Borrelia burgdorferi and sometimes lead to being cured of the disease.^[11]

Stage 2- Early Dissemination Stage

The early dissemination stage of Lyme Disease occurs weeks to months after initial infection if left untreated.^[11] At this point, Borrelia burgdorferi begins to spread throughout the bloodstream and begins to affect other parts of the body beyond the initial bite site.^[11] General symptoms include fever, chills, fatigue, and lymphadenopathy.^[11] The heart may begin to be affected and lead to arrhythmias or myocarditis.^[11] About 4-8% of individuals experience cardiac symptoms.^[8] The musculoskeletal system may also be affected and lead to arthritis development.^[11] Arthritis is common with about 60% of those with Lyme Disease developing the symptom.^[8] Additionally, the nervous system may begin to be affected and present with loss of memory or facial paralysis.^[11] Neurological symptoms affect about 15-20% of individuals who are not treated.^[8]

Stage 3- Late Dissemination Stage

Late disseminated Lyme Disease occurs after one year of initial infection and is also considered chronic Lyme Disease.^[11] Symptoms at this stage are long-term and may include encephalitis, meningitis, and severe arthritis.^[11]^[12] Arthritis at this point in the disease is commonly harsh on individuals' knees.^[12] Other symptoms from previous stages most likely would persist throughout this stage.^[11]

Evasion and Detection of Borrelia burgdorferi

Borrelia burgdorferi Evasion of Host Immune System

Borrelia burgdorferi is particularly good at evading various hosts' immune systems. One way in which the bacteria is able to evade detection is through avoiding immune response by its host through the antigenic variety of the surface level lipoproteins gene, VIsE.^[7] This gene is normally not recognized by the host’s immune system as harmful, thus not attacking it.^[7] Also, The flagella lend to Borrelia burgdorferi’s evasion of hosts' immune systems.^[13] The flagella of Borrelia burgdorferi are attached between the two membranes, unlike other organisms; therefore they can not be targeted by the host's immune system.^[13] Borrelia burgdorferi uses their flagella to propel themselves through the host and evade detection.^[13] Lastly, Borrelia burgdorferi also are able to alter their gene expression in order to adapt to the environment of the host they currently inhabit.^[1] OspA, outer surface protein A, allows for Borrelia burgdorferi to withstand the harsh environment of the tick’s midgut.^[1] However, upon biting a new uninfected host, the expression of OspA decreases.^[1] Upon this decrease, OspC, outer surface protein C, expression increases, which guides the Borrelia burgdorferi to the tick’s salivary glands from the midgut.^[1] The expression of OspC is required for the transmission of Borrelia burgdorferi from tick to its new host. The ability to increase or decrease protein expression levels in order to infect other hosts is an incredible ability of Borrelia burgdorferi.

Current Detection Methods for Lyme Disease

Current methods to diagnose Lyme Disease rely on indirect methods of measuring the presence of Borrelia burgdorferi. Most methods involve serological assays.^[8] However, there are many limitations with serological assays; for example, they can not tell the difference between an active and inactive infection and serological assays look for antibodies that take time for the body to develop.^[8]^[9] Some serological assays use a “two-tiered” system where the first test is positive or borderline positive then another test will be performed to confirm the positive result.^[9] The first test uses enzyme immunoassays (EIA).^[9] Then if positive or borderline positive, the second test will be performed.^[9] The second test includes an immunoblot.^[9] The immunoblot is visually read and considered positive for the detection of Borrelia burgdorferi if there are 2 to 3 bands present within 30 days of onset of symptoms or 5 to 10 bands throughout one’s lifetime.^[9] Testing for Borrelia burgdorferi’s presence is complicated by the fact that many are encouraged to take an initial dose of antibiotics to try to avoid developing Lyme Disease from an infected tick.^[9] This course of antibiotic treatment makes it less likely to detect Borrelia burgdorferi antibodies and decreases the chance of a positive test if infected.^[9]

Current tests lack the necessary sensitivity to antibody levels in order to detect early localized Lyme Disease within the necessary window to treat with antibiotics and cure the disease.^[9] About 40% of those diagnosed with Lyme Disease present with symptoms that suggest a Late Dissemination Stage.^[9] This emphasized the need and importance of a new detection method for Lyme Disease in the early localized stage.^[9] New promising detection methods include a more direct way to test for the presence of Borrelia burgdorferi.

Current Research- New Detection Methods in Development

Figure 5- A. Number of terL present based on number of Borrelia burgdorferi present in the spiked blood sample. Reprinted from Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology. 2021;12. Available: https://www.frontiersin.org/article/10.3389/fmicb.2021.651217

Successful treatment of Lyme Disease is dependent on early and accurate diagnosis. However, with current methods, this is extremely rare and many go through suffering from symptoms and high costs before reaching an accurate diagnosis. Even when they do reach a diagnosis, at this point their Lyme Disease is commonly in the latter two stages and treatment is less effective.

Current research surrounding the early detection of Lyme Disease seems to be promising. New detection methods are being developed through the detection of the multicopy terminase large subunit gene, terL.^[14] TerL is found only in Lyme Disease causing bacteria, which is what makes it such an appealing target for detection of the disease.^[14] The gene terL encodes for the protein terL, which encodes for packing the genome and other essential factors for survival.^[14] Specifically, the terL homologs were found to be mainly present on the cp32 plasmid.^[14] Knowing which plasmid contains the highest concentration of the target protein allows for better detection targeting.^[14] Using terL, the current research group was able to detect even just one single Borrelia burgdorferi cell from a blood sample using PCR.^[14] This is unheard of because typically Borrelia burgdorferi needs time to replication and the new host needs time to develop antibodies to the disease.^[14]

Specifically, Borrelia burgdorferi is released from the host's cells after interactions with stressors, such as antibiotics, which was shown previously, or spontaneously, just demonstrated.^[14] The research group aims to take advantage of the Borrelia burgdorferi leaving the cell in order to detect a more accurate number of Borrelia burgdorferi cells present in a host.^[14] The specific detection method is planning to utilize nine of the thirteen versions of terL that are found within the cp32 plasmid.^[14] By maximizing the number of primers and probes that target the protein, the sensitivity of detection will be greater.^[14]

In order to determine the ability of this new detection method, the research group examined terL presence after qPCR in Borrelia burgdorferi spiked blood samples.^[14] As can be seen in Figure 5A, the greater number of Borrelia burgdorferi present in the spiked blood sample, the greater number of terL copies were observed.^[14] Additionally, in Figure 5B, a linear relationship was found between the amount of Borrelia burgdorferi present in the spiked blood sample and the intensity of terL signals.

This research group is currently working towards clinical trials for utilizing this new detection method of Lyme Disease.^[14] The new method revolutionizes Lyme Disease diagnosis and may allow for thousands of individuals to be diagnosed within the early localized stage of Lyme Disease and seek treatment before great suffering.

Treatment

When diagnosed early enough, Lyme Disease is treatable and curable.^[8] Diagnoses that fall within the early stage of the disease is deemed most likely to be curable.^[8] The antibiotics amoxicillin and doxycycline are commonly used to treat early detection and have not yet developed neurological symptoms.^[15]A course of antibiotics is recommended to last 14 to 28 days depending on the medication, dosage, and individual.^[8] For those with arthritis, which indicates late stages of Lyme Disease, a course of the aforementioned for 28 days is recommended.^[9] Individuals with neurological symptoms are recommended to have treatment via intravenous ceftriaxone.^[9]

If an individual has been previously infected with Borrelia burgdorferi and developed Lyme Disease it is possible to become infected again.^[16] Those who were infected with late Lyme Disease are very unlikely to become reinfected with Lyme Disease again.^[16] Their bodies have developed a stronger and longer-lasting immune response via antibodies to the disease.^[16] However, those who were treated and cured of Lyme Disease in the early stages may be able to become infected again.^[16] This time an individual's body would most likely still have antibodies in your bloodstream, making your infection more difficult to diagnose because.^[16] Common detection methods today, as mentioned above, only can detect Borrelia burgdorferi, not an active infection vs an inactive infection.^[16] The most likely way to diagnose Lyme Disease again would be the appearance of a bull’s eye.^[16]

Unfortunately, it has been found that for those with post-treatment Lyme disease syndrome (PTLDS) no antibiotic treatment is recommended.^[15] Previous work has found that some fatigue can be improved with antibiotic treatment for PTLDS individuals.^[15] Another study found no improvement with antibiotic treatment in PTLDS individuals.^[15] Thus, the overall quality of life does not increase enough that it is recommended to undergo a course of antibiotics for those with PTLDS.^[15]

There are a few treatments in the process of discovery. The use of vancomycin is being examined as it has been shown to almost completely destroy Borrelia burgdorferi in vitro during the stationary phase of the spirochetes.^[9] Vancomycin seems to target the susceptible cell wall synthesis inhibitors in order to destroy Borrelia burgdorferi.^[9] Another group is examining the combination of a few drugs in vitro and currently in mouse models.^[9] They are investigating the combination of Doxycycline, which is currently used to treat early Lyme Disease, Cefoperazone, and Daptomycin.^[9]

Prevention

Figure 6- Prevention methods promoted in order for individuals to avoid becoming infected with Borrelia burgdorferi from ticks and getting Lyme Disease. https://www.cdc.gov/ncezid/dvbd/media/lymedisease.html

One of the best mechanisms for treating Lyme Disease is not getting it to begin with. There are many precautionary steps that can be taken in order to avoid being bitten by an infected tick. Methods of prevention include various factors that help diminish the disease risk.^[9] Lyme Disease control methods commonly fall under two categories, the ecological approach, and the human behavior approach.^[9] Ecological approaches focus on the vector for the disease itself, the tick, and its transmission.^[9] Some suggestions in order to decrease disease risk include reduction of ticks, Lyme Disease hosts (such as white-footed mice or squirrels), and reduction of transmission from hosts to ticks.^[9] Any long-term plan to prevent Lyme disease from an ecological approach must take climate change into consideration because as the temperatures increase the locations in which the tick populations and Borrelia burgdorferi can survive will expand.^[9] Additional methods of Lyme Disease prevention that have been suggested include, mass culling of white-tailed deer or white-footed mice, as they are both reservoirs for the disease.^[9] However, a mass culling has been found to only be effective in isolated populations where Lyme Disease can be completely eliminated.^[9] Even if one reservoir is left with the disease in a population, it will spread again.^[9] Thus, mass cullings are not seen as a viable option.^[9]

The human behavior approach focuses on human behaviors that influence disease risk.^[8] Some suggestions include walking closer to the center of paths in order to avoid bushes, wearing long clothes that cover bare skin, wearing bug spray, if possible modifying the environment, checking for ticks after outdoor activities or daily, and if ticks are found on you properly removing them promptly in order to avoid transmission of Borrelia burgdorferi.^[8]

If one is bitten by a tick and fits the following criteria then antibiotic treatment may be helpful in taking precautionary measures to avoid Borrelia burgdorferi transmission: 1. Incidence of Borrelia burgdorferi infection, or Lyme Disease, is at least 20% of an individual's area, 2. The tick has been attached for at least 36 hours, 3. Antibiotics can be started within 72 hours of removal of the tick.^[8] If individuals do not fit this criterion then antibiotic treatment as a method of prevention is not suggested.^[8] Those who have been bitten by a tick should not get tested for Lyme Disease right away and should be monitored for symptoms closely for 30 days.^[8] As of today, it is not suggested to get tested right away for Lyme Disease because it takes time for the human body to produce antibodies to the disease.^[9] After the 30-day period of time, if experiencing symptoms, individuals may be tested for Lyme Disease as their body would have produced some antibodies by this time.^[8]

Vaccines

Two Lyme Disease vaccines have been created and one of which was placed on the market temporarily; however, there are currently no Lyme Disease vaccines on the market. Previous vaccines include LYMErix and ImuLyme.^[17] Both of these vaccines utilized the outer membrane protein OspA.^[17] The vaccines protect individuals from Lyme Disease by vaccinating against the OspA protein.^[17] As a result of this, those vaccinated would then develop anti-OspA antibodies which would bind and neutralize Borrelia burgdorferi that was transmitted from the tick.^[17] The Borrelia burgdorferi would not be able to penetrate the skin, thus not infecting an individual.^[17]

The first vaccine, LYMErix, was created and placed on the market in December of 1998.^[17] It was found that with two doses there was a 49% efficacy rate and with three doses a 76% efficacy rate.^[17] The three doses must be given over a one-year period of time, and the vaccine is not considered effective until after all three doses.^[17] Thus, people may not be considered safe until after all three doses.^[17]

Despite the vaccine being safe and somewhat effective, LYMErix was taken off the market.^[17] LYMErix was removed in 2002 from the market and after stage three clinical trials in 1998.^[17] LYMErix was removed from the market due to low demand.^[17] This was a result of the vaccine only being marketed to people with high-risk jobs, instead of to the general public as precautionary measures.^[17] Additionally, Borrelia burgdorferi’s geographical location is limited thus limiting the number of individuals within the market for the vaccine.<^[17] Other issues with LYMErix included only having a 76% affection rating, which the FDA deemed as inefficient in preventing Lyme Disease.^[17] Additionally, human clinical trials for the vaccine did not include anyone below the age of 15, which is a group that is considered at higher risk for Lyme Disease.^[17] Controversy also surrounded the company as the vaccine was suspected to cause arthritis.^[17] This claim was dismissed after an investigation by the FDA in 1998.^[17] However, the controversies remained present within conversations surrounding LYMErix.^[17]

ImuLyme was developed in 1998 however never made it to the market for public use.^[18] Two to three doses were necessary for the vaccine to be deemed effective.^[17] However, the controversies remained present within conversations surrounding LYMErix.^[17] With two doses 68% efficacy was found and with three doses 92% efficacy was found.^[17] The efficacy was higher than LYMErix likely due to its difference in composition.^[19] ImuLyme has a chemical composition of purified lipoproteins, which serve as important proteins within the disease.^[19] The purified proteins did not need to absorb the adjuvant, thus allowing it to be overall more effective.^[19]

ImuLyme never made it to the market because the company decided to not produce the vaccine by not pursuing licensure.^[19] Their vaccine was set to hit the market at the same time as LYMErix was and the manufacturers of ImuLyme understood that there was not a large enough demand in the market for them both.^[19] The profit was seen as too small, thus the vaccine was never produced.^[19] Additionally, the vaccine was found to be not as effective in those over the age of 60, which was another age group at high risk of contracting Lyme Disease.<^[17]

Potential future vaccines should take multiple things into consideration in order to be deemed effective and avoid previous vaccine flaws. Due to the nature of the outer surface proteins rapidly changing, it is difficult to target Borrelia burgdorferi and destroy it.^[17] In order to effectively target Borrelia burgdorferi, a potential vaccine needs to find a protein that is continuously expressed.^[17] OspA, outer surface protein A, does just this.^[17] Given that it is expressed throughout all stages of the tick during potential transmission, it fits the criteria for a protein to target with a vaccine.^[17] This is the same outer surface protein that was targeted in the previous vaccines.^[17] While the vaccines worked, they were not as effective as the market would have liked.^[17] Thus, future vaccines need to keep in mind these previous vaccine engineering flaws in order to make a new vaccine that is effective.^[17] However, the new vaccine would be difficult to properly engineer because OspA is only continuously expressed in the tick midgut.^[17] Therefore, the anti-OspA antibodies would need to travel to the midgut in order to destroy the bacteria before traveling to the salary glands of the tick to transmit Borrelia burgdorferi.^[17] Additionally, criteria for a future vaccine from a marketing value perspective include both private and public business coordination to develop the vaccine from a public health standpoint and educate individuals that the components of the vaccine are safe.^[17]

There are currently multiple vaccines in development. These new vaccines are attempting to address the hardships of the previous vaccines, including the efficacy and genetic diversity of Borrelia species.^[9] One vaccine, VLA15, is using six different recombinant OspA proteins in order to target as many spirochetes as possible.^[9] VLA15 is the only vaccine currently in human clinical trials.^[9] Another vaccine is combining antigens from different stages of infection of Borrelia.^[9] This is aimed to target Borrelia that is not killed within the tick midgut or blocked from exiting.^[9] Perhaps the most interesting vaccine currently in the works is not specifically an anti-Borrelia vaccine but rather an anti-tick vaccine.^[9] An anti-tick vaccine is seen as a precautionary step for many tick-borne illnesses.^[9] Ixodes ticks specifically are known to cause 16 human pathogens.^[9] With this anti-tick vaccine, individuals could be protected against all 16 pathogens.^[9]

Conclusion

While previous and current methods for Lyme Disease detection exist, there is a need for current research to expand and put forward a new detection method. Early detection of Lyme Disease is crucial to treating and curing the disease. Borrelia burgdorferi's evasion mechanisms lead to difficulty in developing new methods for detection. Overall, while work exists surrounding Borrelia burgdorferi and Lyme Disease, further investigation is necessary in order to help elevate those lives who are greatly impacted by the disease.

References

↑ ^1.00 ^1.01 ^1.02 ^1.03 ^1.04 ^1.05 ^1.06 ^1.07 ^1.08 ^1.09 ^1.10 ^1.11 ^1.12 ^1.13 ^1.14 ^1.15 ^1.16 ^1.17 ^1.18 ^1.19 ^1.20 ^1.21 ^1.22 ^1.23 ^1.24 ^1.25 ^1.26 ^1.27 Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013
↑ Burgdorfer W, Barbour AG, Hayes SF, Benach JL, Grunwaldt E, Davis JP. Lyme disease-a tick-borne spirochetosis? Science (New York, NY). 1982;216: 1317–1319. doi:10.1126/science.7043737
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↑ Motaleb MA, Corum L, Bono JL, Elias AF, Rosa P, Samuels DS, et al. Borrelia burgdorferi periplasmic flagella have both skeletal and motility functions. Proc Natl Acad Sci U S A. 2000;97: 10899–10904.
↑ Zückert WR. Laboratory Maintenance of Borrelia burgdorferi. Current Protocols in Microbiology. 2007;4: 12C.1.1-12C.1.10. doi:10.1002/9780471729259.mc12c01s4
↑ ^6.0 ^6.1 ^6.2 ^6.3 ^6.4 ^6.5 Fraser CM, Casjens S, Huang WM, Sutton GG, Clayton R, Lathigra R, et al. Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi. Nature. 1997;390: 580–586. doi:10.1038/37551
↑ ^7.0 ^7.1 ^7.2 ^7.3 ^7.4 ^7.5 ^7.6 ^7.7 ^7.8 ^7.9 Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of Borrelia burgdorferi. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140
↑ ^8.00 ^8.01 ^8.02 ^8.03 ^8.04 ^8.05 ^8.06 ^8.07 ^8.08 ^8.09 ^8.10 ^8.11 ^8.12 ^8.13 ^8.14 ^8.15 ^8.16 ^8.17 ^8.18 ^8.19 ^8.20 ^8.21 ^8.22 ^8.23 ^8.24 ^8.25 ^8.26 ^8.27 ^8.28 ^8.29 ^8.30 ^8.31 ^8.32 ^8.33 ^8.34 ^8.35 ^8.36 ^8.37 ^8.38 Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3
↑ ^9.00 ^9.01 ^9.02 ^9.03 ^9.04 ^9.05 ^9.06 ^9.07 ^9.08 ^9.09 ^9.10 ^9.11 ^9.12 ^9.13 ^9.14 ^9.15 ^9.16 ^9.17 ^9.18 ^9.19 ^9.20 ^9.21 ^9.22 ^9.23 ^9.24 ^9.25 ^9.26 ^9.27 ^9.28 ^9.29 ^9.30 ^9.31 ^9.32 ^9.33 ^9.34 ^9.35 ^9.36 ^9.37 ^9.38 ^9.39 ^9.40 ^9.41 Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554
↑ ^10.0 ^10.1 ^10.2 CDC. Transmission of Lyme disease | CDC. In: Centers for Disease Control and Prevention [Internet. 29 Jan 2020 [cited 18 Apr 2022]. Available: https://www.cdc.gov/lyme/transmission/index.html]
↑ ^11.00 ^11.01 ^11.02 ^11.03 ^11.04 ^11.05 ^11.06 ^11.07 ^11.08 ^11.09 ^11.10 ^11.11 ^11.12 ^11.13 ^11.14 ^11.15 ^11.16 ^11.17 Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3
↑ ^12.0 ^12.1 ^12.2 ^12.3 Skar GL, Simonsen KA. Lyme Disease. StatPearls. Treasure Island (FL): StatPearls Publishing; 2022. Available: http://www.ncbi.nlm.nih.gov/books/NBK431066/
↑ ^13.0 ^13.1 ^13.2 1. Berndtson K. Review of evidence for immune evasion and persistent infection in Lyme disease. Int J Gen Med. 2013;6: 291–306. doi:10.2147/IJGM.S44114
↑ ^14.00 ^14.01 ^14.02 ^14.03 ^14.04 ^14.05 ^14.06 ^14.07 ^14.08 ^14.09 ^14.10 ^14.11 ^14.12 ^14.13 Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.
↑ ^15.0 ^15.1 ^15.2 ^15.3 ^15.4 NIH. Lyme Disease Antibiotic Treatment Research | NIH: National Institute of Allergy and Infectious Diseases. 2018 [cited 18 Apr 2022. Available: https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research]
↑ ^16.0 ^16.1 ^16.2 ^16.3 ^16.4 ^16.5 ^16.6 Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43:1089.
↑ ^17.00 ^17.01 ^17.02 ^17.03 ^17.04 ^17.05 ^17.06 ^17.07 ^17.08 ^17.09 ^17.10 ^17.11 ^17.12 ^17.13 ^17.14 ^17.15 ^17.16 ^17.17 ^17.18 ^17.19 ^17.20 ^17.21 ^17.22 ^17.23 ^17.24 ^17.25 ^17.26 ^17.27 ^17.28 ^17.29 ^17.30 ^17.31 ^17.32 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116
↑ Nesich H. The History Behind the First Lyme Disease Vaccine – Tick Talk. [cited 18 Apr 2022. Available: https://sites.newpaltz.edu/ticktalk/ottaway-2014-lyme-disease-investigation/history-behind-the-first-lyme-disease-vaccine/]
↑ ^19.0 ^19.1 ^19.2 ^19.3 ^19.4 ^19.5 Dattwyler RJ, Gomes-Solecki M. The year that shaped the outcome of the OspA vaccine for human Lyme disease. npj Vaccines. 2022;7: 1–5. doi:10.1038/s41541-022-00429-5

Authored for BIOL 238 Microbiology, taught by Joan Slonczewski, 2022, Kenyon College

[maroon-1] 1.00 ^1.01 ^1.02 ^1.03 ^1.04 ^1.05 ^1.06 ^1.07 ^1.08 ^1.09 ^1.10 ^1.11 ^1.12 ^1.13 ^1.14 ^1.15 ^1.16 ^1.17 ^1.18 ^1.19 ^1.20 ^1.21 ^1.22 ^1.23 ^1.24 ^1.25 ^1.26 ^1.27 Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013

[yellow1-2] Burgdorfer W, Barbour AG, Hayes SF, Benach JL, Grunwaldt E, Davis JP. Lyme disease-a tick-borne spirochetosis? Science (New York, NY). 1982;216: 1317–1319. doi:10.1126/science.7043737

[yellow2-3] 3.0 ^3.1 ^3.2 Motaleb MA, Liu J, Wooten RM. Spirochetal motility and chemotaxis in the natural enzootic cycle and development of Lyme disease. Current Opinion in Microbiology. 2015;28: 106–113. doi:10.1016/j.mib.2015.09.006

[yellow3-4] Motaleb MA, Corum L, Bono JL, Elias AF, Rosa P, Samuels DS, et al. Borrelia burgdorferi periplasmic flagella have both skeletal and motility functions. Proc Natl Acad Sci U S A. 2000;97: 10899–10904.

[yellow4-5] Zückert WR. Laboratory Maintenance of Borrelia burgdorferi. Current Protocols in Microbiology. 2007;4: 12C.1.1-12C.1.10. doi:10.1002/9780471729259.mc12c01s4

[yellow5-6] 6.0 ^6.1 ^6.2 ^6.3 ^6.4 ^6.5 Fraser CM, Casjens S, Huang WM, Sutton GG, Clayton R, Lathigra R, et al. Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi. Nature. 1997;390: 580–586. doi:10.1038/37551

[red-7] 7.0 ^7.1 ^7.2 ^7.3 ^7.4 ^7.5 ^7.6 ^7.7 ^7.8 ^7.9 Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of Borrelia burgdorferi. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140

[navy-8] 8.00 ^8.01 ^8.02 ^8.03 ^8.04 ^8.05 ^8.06 ^8.07 ^8.08 ^8.09 ^8.10 ^8.11 ^8.12 ^8.13 ^8.14 ^8.15 ^8.16 ^8.17 ^8.18 ^8.19 ^8.20 ^8.21 ^8.22 ^8.23 ^8.24 ^8.25 ^8.26 ^8.27 ^8.28 ^8.29 ^8.30 ^8.31 ^8.32 ^8.33 ^8.34 ^8.35 ^8.36 ^8.37 ^8.38 Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3

[pink-9] 9.00 ^9.01 ^9.02 ^9.03 ^9.04 ^9.05 ^9.06 ^9.07 ^9.08 ^9.09 ^9.10 ^9.11 ^9.12 ^9.13 ^9.14 ^9.15 ^9.16 ^9.17 ^9.18 ^9.19 ^9.20 ^9.21 ^9.22 ^9.23 ^9.24 ^9.25 ^9.26 ^9.27 ^9.28 ^9.29 ^9.30 ^9.31 ^9.32 ^9.33 ^9.34 ^9.35 ^9.36 ^9.37 ^9.38 ^9.39 ^9.40 ^9.41 Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554

[CDC-10] 10.0 ^10.1 ^10.2 CDC. Transmission of Lyme disease | CDC. In: Centers for Disease Control and Prevention [Internet. 29 Jan 2020 [cited 18 Apr 2022]. Available: https://www.cdc.gov/lyme/transmission/index.html]

[yellow7-11] 11.00 ^11.01 ^11.02 ^11.03 ^11.04 ^11.05 ^11.06 ^11.07 ^11.08 ^11.09 ^11.10 ^11.11 ^11.12 ^11.13 ^11.14 ^11.15 ^11.16 ^11.17 Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3

[lightpurple-12] 12.0 ^12.1 ^12.2 ^12.3 Skar GL, Simonsen KA. Lyme Disease. StatPearls. Treasure Island (FL): StatPearls Publishing; 2022. Available: http://www.ncbi.nlm.nih.gov/books/NBK431066/

[bluenew-13] 13.0 ^13.1 ^13.2 1. Berndtson K. Review of evidence for immune evasion and persistent infection in Lyme disease. Int J Gen Med. 2013;6: 291–306. doi:10.2147/IJGM.S44114

[orange-14] 14.00 ^14.01 ^14.02 ^14.03 ^14.04 ^14.05 ^14.06 ^14.07 ^14.08 ^14.09 ^14.10 ^14.11 ^14.12 ^14.13 Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.

[brightgreen-15] 15.0 ^15.1 ^15.2 ^15.3 ^15.4 NIH. Lyme Disease Antibiotic Treatment Research | NIH: National Institute of Allergy and Infectious Diseases. 2018 [cited 18 Apr 2022. Available: https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research]

[darkpurple-16] 16.0 ^16.1 ^16.2 ^16.3 ^16.4 ^16.5 ^16.6 Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43:1089.

[purple-17] 17.00 ^17.01 ^17.02 ^17.03 ^17.04 ^17.05 ^17.06 ^17.07 ^17.08 ^17.09 ^17.10 ^17.11 ^17.12 ^17.13 ^17.14 ^17.15 ^17.16 ^17.17 ^17.18 ^17.19 ^17.20 ^17.21 ^17.22 ^17.23 ^17.24 ^17.25 ^17.26 ^17.27 ^17.28 ^17.29 ^17.30 ^17.31 ^17.32 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116

[lightgray-18] Nesich H. The History Behind the First Lyme Disease Vaccine – Tick Talk. [cited 18 Apr 2022. Available: https://sites.newpaltz.edu/ticktalk/ottaway-2014-lyme-disease-investigation/history-behind-the-first-lyme-disease-vaccine/]

[lightpink-19] 19.0 ^19.1 ^19.2 ^19.3 ^19.4 ^19.5 Dattwyler RJ, Gomes-Solecki M. The year that shaped the outcome of the OspA vaccine for human Lyme disease. npj Vaccines. 2022;7: 1–5. doi:10.1038/s41541-022-00429-5

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@@ Line 2: / Line 2: @@
 ==Overview==
-[[Image:Borrelia_Pic.jpeg|thumb|300px|right|Figure 1- <i>Borrelia burgdorferi</i> bacteria under a scanning electron micrograph.  Image taken by Claudia Molins at the CDC, 2011. [http://phil.cdc.gov/phil/details.asp?pid=13176}.]]
+[[Image:Borrelia_Pic.jpeg|thumb|300px|right|Figure 1- <i>Borrelia burgdorferi</i> bacteria under a scanning electron micrograph.  Image taken by Claudia Molins at the CDC, 2011. http://phil.cdc.gov/phil/details.asp?pid=13176.]]
-[[Image: https://acs-h.assetsadobe.com/is/image//content/dam/cen/96/35/09635-feature2-Lymebacteriacxd.jpg/?$responsive$&wid=700&qlt=90,0&resMode=sharp2|thumb|300px|right| CAPTION]]
 <br>By Roya Best
@@ Line 11: / Line 8: @@
 ==Genetics==
-The genome of <i>Borrelia burgdorferi</i> is a linear chromosome with many smaller plasmids that are both linear and circular.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The linear chromosome is about 950 kb and the linear and circular plasmids range from 9 to 62 kb, which all encode 853 genes.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref><ref name=yellow5>[https://www.nature.com/articles/37551 Fraser CM, Casjens S, Huang WM, Sutton GG, Clayton R, Lathigra R, et al. Genomic sequence of a Lyme disease spirochaete, <i>Borrelia burgdorferi</i>. Nature. 1997;390: 580–586. doi:10.1038/37551]</ref>   The genome of <i>Borrelia burgdorferi</i> was the third ever genome sequenced.<ref name=yellow5>[https://www.nature.com/articles/37551 Fraser CM, Casjens S, Huang WM, Sutton GG, Clayton R, Lathigra R, et al. Genomic sequence of a Lyme disease spirochaete, <i>Borrelia burgdorferi</i>. Nature. 1997;390: 580–586. doi:10.1038/37551]</ref>  Linear chromosomes are not common in bacteria, however, in <i>Borrelia burgdorferi</i> it seems to provide an advantage that has continued to allow the linear chromosome to persist.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The <i>Borrelia burgdorferi</i> genetic sequence shows that the flagella are hidden between the two membranes compared to other organisms that have it externally radiating outward.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The flagella are strategically positioned in order to provide <i>Borrelia burgdorferi</i> an advantage in hiding from the host immune system, as this is critical in its survival.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>
+[[File:genetics.png|thumb|300px|right|Figure 2- Chromosome and plasmid lengths and shape demonstrated. The main chromosome of <i>Borrelia burgdorferi</i> is linear, while the plasmids of <i>Borrelia burgdorferi</i> are both linear and circular. Reprinted from Glöckner G, Lehmann R, Romualdi A, Pradella S, Schulte-Spechtel U, Schilhabel M, et al. Comparative analysis of the Borrelia garinii genome. Nucleic acids research. 2004;32: 6038–46. doi:10.1093/nar/gkh953]]
+The genome of <i>Borrelia burgdorferi</i> is a linear chromosome with many smaller plasmids that are both linear and circular.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The linear chromosome is about 950 kb and the linear and circular plasmids range from 9 to 62 kb, which all encode 853 genes.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref><ref name=yellow5>[https://www.nature.com/articles/37551 Fraser CM, Casjens S, Huang WM, Sutton GG, Clayton R, Lathigra R, et al. Genomic sequence of a Lyme disease spirochaete, <i>Borrelia burgdorferi</i>. Nature. 1997;390: 580–586. doi:10.1038/37551]</ref>   The genome of <i>Borrelia burgdorferi</i> was the third ever genome sequenced.<ref name=yellow5>[https://www.nature.com/articles/37551 Fraser CM, Casjens S, Huang WM, Sutton GG, Clayton R, Lathigra R, et al. Genomic sequence of a Lyme disease spirochaete, <i>Borrelia burgdorferi</i>. Nature. 1997;390: 580–586. doi:10.1038/37551]</ref>  Linear chromosomes are not common in bacteria, however, in <i>Borrelia burgdorferi</i> it seems to provide an advantage that has continued to allow the linear chromosome to persist.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The <i>Borrelia burgdorferi</i> genetic sequence shows that the flagella are hidden between the two membranes compared to other organisms that have it externally radiating outward.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The flagella are strategically positioned in order to provide <i>Borrelia burgdorferi</i> an advantage in hiding from the host immune system, as this is critical in its survival.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>
 <i>Borrelia burgdorferi</i> lacks the classic genes to synthesize amino acids, fatty acids, enzyme cofactors, and nucleotides.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  It takes advantage of its host and obtains these important materials.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The inability to synthesize these things is likely lost in coevolution with ticks and other hosts.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of <i>Borrelia burgdorferi</i>. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref>  Additionally,  <i>Borrelia burgdorferi</i> lacks the genes to use the citric acid cycle, oxidative phosphorylation, and cellular biosynthesis.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of <i>Borrelia burgdorferi</i>. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref><ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref> <i>Borrelia burgdorferi</i>, however, has the genes for and derives its energy from glycolysis and fermentation of sugars.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of <i>Borrelia burgdorferi</i>. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref>
@@ Line 18: / Line 17: @@
 ==Lyme Disease History and Overview==
-Lyme Disease is an enzootic vector-borne disease that is transmitted by Ixodes tick.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref> Lyme Disease was first discovered by Doctor Alan Steere in 1977 when he noticed that people were being infected with an unknown pathogen in the same geographic location during the same time of the year presenting with the same symptoms.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>   The first confirmed case was in Lyme, Connecticut, thus providing the name of the Disease.<ref name=yellow5>[https://www.nature.com/articles/37551 Fraser CM, Casjens S, Huang WM, Sutton GG, Clayton R, Lathigra R, et al. Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi. Nature. 1997;390: 580–586. doi:10.1038/37551]</ref>  In 1981 it was finally discovered that Borrelia genus bacteria were the causative agents of Lyme Disease.<ref name=yellow5>[https://www.nature.com/articles/37551 Fraser CM, Casjens S, Huang WM, Sutton GG, Clayton R, Lathigra R, et al. Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi. Nature. 1997;390: 580–586. doi:10.1038/37551]</ref>
+Lyme Disease is an enzootic vector-borne disease that is transmitted by Ixodes ticks.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref> Lyme Disease was first discovered by Doctor Alan Steere in 1977 when he noticed that people were being infected with an unknown pathogen in the same geographic location during the same time of the year presenting with the same symptoms.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>   The first confirmed case was in Lyme, Connecticut, thus providing the name of the Disease.<ref name=yellow5>[https://www.nature.com/articles/37551 Fraser CM, Casjens S, Huang WM, Sutton GG, Clayton R, Lathigra R, et al. Genomic sequence of a Lyme disease spirochaete, <i>Borrelia burgdorferi</i>. Nature. 1997;390: 580–586. doi:10.1038/37551]</ref>  In 1981 it was finally discovered that Borrelia genus bacteria were the causative agents of Lyme Disease.<ref name=yellow5>[https://www.nature.com/articles/37551 Fraser CM, Casjens S, Huang WM, Sutton GG, Clayton R, Lathigra R, et al. Genomic sequence of a Lyme disease spirochaete, <i>Borrelia burgdorferi</i>. Nature. 1997;390: 580–586. doi:10.1038/37551]</ref>
-There are a few Borrelia species that can cause Lyme Disease, however, Borrelia burgdorferi is the most common in the US.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  Lyme Disease is the leading vector-borne disease in the US.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  There are an estimated 476,000 cases each year of Lyme Disease in the US according to numbers from 2010 to 2018.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  However, this is most likely an underestimate because Lyme Disease is difficult to diagnose.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Lyme Disease is endemic to the US, Europe, and Asia.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  Most cases are reported during the Spring and Summer months due to the life cycle of the reservoir, the Ixodes ticks.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref><ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  Common animals that can become infected with Borrelia burgdorferi are white-footed mice, chipmunks, dogs, white-tailed deer, squirrels, horses,  opossums, and raccoons.<br><b>INSERT BOOK CITATION HERE</b>
+There are a few Borrelia species that can cause Lyme Disease, however, <i>Borrelia burgdorferi</i> is the most common in the US.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  Lyme Disease is the leading vector-borne disease in the US.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  There are an estimated 476,000 cases each year of Lyme Disease in the US according to numbers from 2010 to 2018.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  However, this is most likely an underestimate because Lyme Disease is difficult to diagnose.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Lyme Disease is endemic to the US, Europe, and Asia.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  Most cases are reported during the Spring and Summer months due to the life cycle of the reservoir, the Ixodes ticks.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref><ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  Common animals that can become infected with <i>Borrelia burgdorferi</i> are white-footed mice, chipmunks, dogs, white-tailed deer, squirrels, horses,  opossums, and raccoons.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>
 Research surrounding Lyme Disease is sparse due to the lack of federal funding.  The annual NIH investment in research is much lower than in other infectious diseases.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Thirty million dollars a year is allocated to Lyme Disease research which affects over 470,000 individuals annually.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  However, 36 million dollars is allocated to West Nile Virus which only affects about 3,000 individuals and 202 million dollars is allocated to Malaria which only affects under 2,000 individuals.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  The lack of funding surrounding Lyme Disease is highly controversial and why individuals with the disease commonly suffer due to improper diagnosis and must tolerate its symptoms.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>
 ==Transmission==
-Ticks become infected with Borrelia burgdorferi when they have a blood meal from an infected reservoir, such as a white-footed mouse or chipmunk.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  When an infected tick bites an animal or human, Borrelia burgdorferi will migrate from the tick’s midgut to the salivary glands and then into the bloodstream of the new host.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The spirochete then travels from the bloodstream to various tissues within the new host.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The location in which Borrelia burgdorferi lands is where the most symptoms will be experienced.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  While no virulence factors are found within Borrelia burgdorferi, symptoms will occur as a result of the inflammatory response and damage the bacteria causes when it replicates.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>
+Ticks become infected with <i>Borrelia burgdorferi</i> when they have a blood meal from an infected reservoir, such as a white-footed mouse or chipmunk.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  When an infected tick bites an animal or human, <i>Borrelia burgdorferi</i> will migrate from the tick’s midgut to the salivary glands and then into the bloodstream of the new host.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The spirochete then travels from the bloodstream to various tissues within the new host.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The location in which <i>Borrelia burgdorferi</i> lands is where the most symptoms will be experienced.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  While no virulence factors are found within <i>Borrelia burgdorferi</i>, symptoms will occur as a result of the inflammatory response and damage the bacteria causes when it replicates.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref> Ticks can attach to any part of the animal or human in order to take a blood meal and infect the individual with <i>Borrelia burgdorferi</i>.<ref name=CDC>[https://www.cdc.gov/lyme/transmission/index.html CDC. Transmission of Lyme disease | CDC. In: Centers for Disease Control and Prevention [Internet]. 29 Jan 2020 [cited 18 Apr 2022]. Available: https://www.cdc.gov/lyme/transmission/index.html]</ref>  However, on humans, ticks particularly like to attach to hard-to-see places.<ref name=CDC>[https://www.cdc.gov/lyme/transmission/index.html CDC. Transmission of Lyme disease | CDC. In: Centers for Disease Control and Prevention [Internet]. 29 Jan 2020 [cited 18 Apr 2022]. Available: https://www.cdc.gov/lyme/transmission/index.html]</ref>  These areas include behind the near, on the scalp, armpits, and behind the knees.<ref name=CDC>[https://www.cdc.gov/lyme/transmission/index.html CDC. Transmission of Lyme disease | CDC. In: Centers for Disease Control and Prevention [Internet]. 29 Jan 2020 [cited 18 Apr 2022]. Available: https://www.cdc.gov/lyme/transmission/index.html]</ref>
 Acquiring the disease depends on many factors, including, density, distribution, and prevalence of infected ticks in the individual's area.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   Cases of Lyme Disease are the most common in the Northeast and Northern Central states within the US.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   The most reported cases occur May through August due to the life cycle of ticks, tick feeding time, and increase in human activity outdoors.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   A tick must be attached to its new host for over 36 hours in order to transmit the disease.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   Adult ticks and nymph ticks can transmit the disease.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   However, it is much more likely to be infected by a nymph tick because of its small size and the likelihood of remaining attached for over 36 hours.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>
+==Life Cycle==
+[[File:rhg.webp|thumb|500px|left|Figure 3- Life cycle of <i>Borrelia burgdorferi</i> and <i>Ixodes</i> ticks.  Larval ticks become infected with <i>Borrelia burgdorferi</i>, molt into nymphs, bite an uninfected host, and transmit <i>Borrelia burgdorferi</i>, leading to Lyme Disease. Reprinted from Kurokawa C, Lynn GE, Pedra JHF, Pal U, Narasimhan S, Fikrig E. Interactions between Borrelia burgdorferi and ticks. Nat Rev Microbiol. 2020;18: 587–600. doi:10.1038/s41579-020-0400-5]]
-<br><b>INSERT CDC INFO AND FIGURE</b>
+===Tick life cycle===
-==Life Cycle==
+Ticks are the only known natural agents that can infect animals and humans with <i>Borrelia burgdorferi</i>.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The tick genus Ixodes can become infected with and transmit <i>Borrelia burgdorferi</i> between hosts and reservoirs.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>
-Tick life cycle-
-Ticks are the only known natural agents that can infect animals and humans with Borrelia burgdorferi.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The tick genus Ixodes can become infected with and transmit Borrelia burgdorferi between hosts and reservoirs.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>
-The life cycle of the Ixodes ticks heavily influences the transmission of Borrelia burgdorferi between various animals and humans.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The tick has a life span of two years and undergoes different life stages.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with Borrelia burgdorferi. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The egg phase of ticks has no influence on Lyme Disease and Borrelia burgdorferi can not be contracted during this stage.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   The larva stage is when ticks must take a blood meal to survive and grow, thus feeding on small animals, usually mice.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   This stage is critical to Lyme Disease as ticks can become infected with Borrelia burgdorferi.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   The combination of taking a blood meal and feeding upon white-footed mice is key because white-footed mice are known as one of the main reservoirs for which ticks become infected with Borrelia burgdorferi.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   The next stage of a tick’s life cycle is the nymph stage.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   At this stage, ticks can infect others with Borrelia burgdorferi.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   At the nymph stage, ticks also can infect small animals and humans.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   Nymphs are extremely small in size and can evade detection by humans, thus being attached long enough to infect humans with Borrelia burgdorferi.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   Ticks during the nymph stage feed in the spring and summer, when Lyme Disease cases are reported the highest.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   After the nymph stage, ticks molt into adults.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   Adult ticks can infect other animals and humans with Borrelia burgdorferi.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   However, it is not common for adult ticks to transmit Borrelia burgdorferi to humans because of their large size, which allows them to be easily seen and removed.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>
+The life cycle of the Ixodes ticks heavily influences the transmission of <i>Borrelia burgdorferi</i> between various animals and humans.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The tick has a life span of two years and undergoes different life stages.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  The egg phase of ticks has no influence on Lyme Disease and <i>Borrelia burgdorferi</i> can not be contracted during this stage.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   The larva stage is when ticks must take a blood meal to survive and grow, thus feeding on small animals, usually mice.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   This stage is critical to Lyme Disease as ticks can become infected with <i>Borrelia burgdorferi</i>.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   The combination of taking a blood meal and feeding upon white-footed mice is key because white-footed mice are known as one of the main reservoirs for which ticks become infected with <i>Borrelia burgdorferi</i>.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   The next stage of a tick’s life cycle is the nymph stage.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   At this stage, ticks can infect others with <i>Borrelia burgdorferi</i>.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   At the nymph stage, ticks also can infect small animals and humans.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   Nymphs are extremely small in size and can evade detection by humans, thus being attached long enough to infect humans with <i>Borrelia burgdorferi</i>.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   Ticks during the nymph stage feed in the spring and summer, when Lyme Disease cases are reported the highest.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   After the nymph stage, ticks molt into adults.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   Adult ticks can infect other animals and humans with <i>Borrelia burgdorferi</i>.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>   However, it is not common for adult ticks to transmit <i>Borrelia burgdorferi</i> to humans because of their large size, which allows them to be easily seen and removed.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>
-Lyme Disease life cycle-
+===Lyme Disease life cycle===
-Lyme disease itself goes through a life cycle during the transmission of Borrelia burgdorferi between hosts and reservoirs.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of Borrelia burgdorferi. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref>  Larva or nymphs acquire Borrelia burgdorferi during their first blood meal from an infected host.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of Borrelia burgdorferi. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref>  Once infected, Borrelia burgdorferi persists in the tick’s midgut.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of Borrelia burgdorferi. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref>  When the infected nymph bites an uninfected animal the bite triggers the Borrelia burgdorferi to replicate, escape from the tick’s midgut, and exit through the salivary glands of the tick to another host.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of Borrelia burgdorferi. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref>  This life cycle of Borrelia burgdorferi and Lyme Disease thus completes the enzootic cycle.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of Borrelia burgdorferi. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref>
-<br><b>RED HAS GREAT FIGURE ADD</b>
+Lyme disease itself goes through a life cycle during the transmission of <i>Borrelia burgdorferi</i> between hosts and reservoirs.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of <i>Borrelia burgdorferi</i>. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref>  Larva or nymphs acquire <i>Borrelia burgdorferi</i> during their first blood meal from an infected host.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of <i>Borrelia burgdorferi</i>. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref>  Once infected, <i>Borrelia burgdorferi</i> persists in the tick’s midgut.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of <i>Borrelia burgdorferi</i>. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref>  When the infected nymph bites an uninfected animal the bite triggers the <i>Borrelia burgdorferi</i> to replicate, escape from the tick’s midgut, and exit through the salivary glands of the tick to another host.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of <i>Borrelia burgdorferi</i>. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref>  This life cycle of <i>Borrelia burgdorferi</i> and Lyme Disease thus completes the enzootic cycle.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of <i>Borrelia burgdorferi</i>. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref>
 ==Stages and Symptoms==
-There are three stages to Lyme Disease: early localized stage, early disseminated stage, and late disseminated stage.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref>  With each stage, new symptoms develop, and old ones may persist or disappear.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref>
+[[File:Bullseye.png|thumb|300px|right|Figure 4- An example of the "Bull's Eye" rash that appears in 70% of those infected with <i>Borrelia burgdorferi</i> https://www.cdc.gov/lyme/signs_symptoms/index.html]]
+There are three stages of Lyme Disease: early localized stage, early disseminated stage, and late disseminated stage.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref>  With each stage, new symptoms develop, and old ones may persist or disappear.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref>
+===Stage 1- Early Localized Stage===
+Early localized Lyme Disease occurs three days to one month after the initial tick bite.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref>  The local area of the bite will be the area that experiences the most symptoms.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref>  About 70% of individuals will develop a “bull’s eye” rash.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref><ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  This rash is characteristic of Lyme Disease and commonly leads to diagnosis.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref><ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  It may get as large as 15 cm and last up to three weeks if untreated.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref><ref name=lightpurple>[https://www.ncbi.nlm.nih.gov/books/NBK431066/#:~:text=Like%20syphilis%2C%20Lyme%20is%20classified,12%20months%20of%20the%20infection Skar GL, Simonsen KA. Lyme Disease. StatPearls. Treasure Island (FL): StatPearls Publishing; 2022. Available: http://www.ncbi.nlm.nih.gov/books/NBK431066/]</ref>  Symptoms at this stage include flu-like symptoms, such as fever, eye redness, neck stiffness, and headaches.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref><ref name=lightpurple>[https://www.ncbi.nlm.nih.gov/books/NBK431066/#:~:text=Like%20syphilis%2C%20Lyme%20is%20classified,12%20months%20of%20the%20infection Skar GL, Simonsen KA. Lyme Disease. StatPearls. Treasure Island (FL): StatPearls Publishing; 2022. Available: http://www.ncbi.nlm.nih.gov/books/NBK431066/]</ref>  Antibiotics at this stage are the most effective and can prevent further growth of <i>Borrelia burgdorferi</i> and sometimes lead to being cured of the disease.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref>
+===Stage 2- Early Dissemination Stage===
+The early dissemination stage of Lyme Disease occurs weeks to months after initial infection if left untreated.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref>  At this point, <i>Borrelia burgdorferi</i> begins to spread throughout the bloodstream and begins to affect other parts of the body beyond the initial bite site.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref>  General symptoms include fever, chills, fatigue, and lymphadenopathy.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref>  The heart may begin to be affected and lead to arrhythmias or myocarditis.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref>  About 4-8% of individuals experience cardiac symptoms.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  The musculoskeletal system may also be affected and lead to arthritis development.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref>  Arthritis is common with about 60% of those with Lyme Disease developing the symptom.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  Additionally, the nervous system may begin to be affected and present with loss of memory or facial paralysis.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref>  Neurological symptoms affect about 15-20% of individuals who are not treated.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>
+===Stage 3- Late Dissemination Stage===
+Late disseminated Lyme Disease occurs after one year of initial infection and is also considered chronic Lyme Disease.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref>  Symptoms at this stage are long-term and may include encephalitis, meningitis, and severe arthritis.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref><ref name=lightpurple>[https://www.ncbi.nlm.nih.gov/books/NBK431066/#:~:text=Like%20syphilis%2C%20Lyme%20is%20classified,12%20months%20of%20the%20infection Skar GL, Simonsen KA. Lyme Disease. StatPearls. Treasure Island (FL): StatPearls Publishing; 2022. Available: http://www.ncbi.nlm.nih.gov/books/NBK431066/]</ref>  Arthritis at this point in the disease is commonly harsh on individuals' knees.<ref name=lightpurple>[https://www.ncbi.nlm.nih.gov/books/NBK431066/#:~:text=Like%20syphilis%2C%20Lyme%20is%20classified,12%20months%20of%20the%20infection Skar GL, Simonsen KA. Lyme Disease. StatPearls. Treasure Island (FL): StatPearls Publishing; 2022. Available: http://www.ncbi.nlm.nih.gov/books/NBK431066/]</ref>  Other symptoms from previous stages most likely would persist throughout this stage.<ref name=yellow7>Tortora, Gerard J.; Funke, Berdell R.; Case, Christine L. (2013). Microbiology: An Introduction. United States of America: Pearson Education, Inc. pp. 658–659. ISBN 978-0-321-73360-3</ref>
+==Evasion and Detection of <i>Borrelia burgdorferi</i>==
+===<i>Borrelia burgdorferi</i> Evasion of Host Immune System===
+<i>Borrelia burgdorferi</i> is particularly good at evading various hosts' immune systems. One way in which the bacteria is able to evade detection is through avoiding immune response by its host through the antigenic variety of the surface level lipoproteins gene, <i>VIsE</i>.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of <i>Borrelia burgdorferi</i>. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref>  This gene is normally not recognized by the host’s immune system as harmful, thus not attacking it.<ref name=red>[https://pubmed.ncbi.nlm.nih.gov/22974303/#:~:text=The%20current%20assemblage%20of%20B,predominantly%20composed%20of%20linear%20replicons Brisson D, Drecktrah D, Eggers CH, Samuels DS. Genetics of <i>Borrelia burgdorferi</i>. Annu Rev Genet. 2012;46: 515–536. doi:10.1146/annurev-genet-011112-112140]</ref> Also, The flagella lend to <i>Borrelia burgdorferi</i>’s evasion of hosts' immune systems.<ref name=bluenew>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636972/ 1. Berndtson K. Review of evidence for immune evasion and persistent infection in Lyme disease. Int J Gen Med. 2013;6: 291–306. doi:10.2147/IJGM.S44114]</ref> The flagella of <i>Borrelia burgdorferi</i> are attached between the two membranes, unlike other organisms; therefore they can not be targeted by the host's immune system.<ref name=bluenew>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636972/ 1. Berndtson K. Review of evidence for immune evasion and persistent infection in Lyme disease. Int J Gen Med. 2013;6: 291–306. doi:10.2147/IJGM.S44114]</ref>  <i>Borrelia burgdorferi</i> uses their flagella to propel themselves through the host and evade detection.<ref name=bluenew>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636972/ 1. Berndtson K. Review of evidence for immune evasion and persistent infection in Lyme disease. Int J Gen Med. 2013;6: 291–306. doi:10.2147/IJGM.S44114]</ref>  Lastly, <i>Borrelia burgdorferi</i> also are able to alter their gene expression in order to adapt to the environment of the host they currently inhabit.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  OspA, outer surface protein A, allows for <i>Borrelia burgdorferi</i> to withstand the harsh environment of the tick’s midgut.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  However, upon biting a new uninfected host, the expression of OspA decreases.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>  Upon this decrease, OspC, outer surface protein C, expression increases, which guides the <i>Borrelia burgdorferi</i> to the tick’s salivary glands from the midgut.<ref name=maroon>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440571/ Tilly K, Rosa PA, Stewart PE. Biology of Infection with <i>Borrelia burgdorferi</i>. Infect Dis Clin North Am. 2008;22: 217–234. doi:10.1016/j.idc.2007.12.013]</ref>   The expression of OspC is required for the transmission of <i>Borrelia burgdorferi</i> from tick to its new host. The ability to increase or decrease protein expression levels in order to infect other hosts is an incredible ability of <i>Borrelia burgdorferi</i>.
+===Current Detection Methods for Lyme Disease===
+Current methods to diagnose Lyme Disease rely on indirect methods of measuring the presence of <i>Borrelia burgdorferi</i>.  Most methods involve serological assays.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  However, there are many limitations with serological assays; for example, they can not tell the difference between an active and inactive infection and serological assays look for antibodies that take time for the body to develop.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref><ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Some serological assays use a “two-tiered” system where the first test is positive or borderline positive then another test will be performed to confirm the positive result.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  The first test uses enzyme immunoassays (EIA).<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Then if positive or borderline positive, the second test will be performed.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  The second test includes an immunoblot.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  The immunoblot is visually read and considered positive for the detection of <i>Borrelia burgdorferi</i> if there are 2 to 3 bands present within 30 days of onset of symptoms or 5 to 10 bands throughout one’s lifetime.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Testing for <i>Borrelia burgdorferi</i>’s presence is complicated by the fact that many are encouraged to take an initial dose of antibiotics to try to avoid developing Lyme Disease from an infected tick.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  This course of antibiotic treatment makes it less likely to detect <i>Borrelia burgdorferi</i> antibodies and decreases the chance of a positive test if infected.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>
+Current tests lack the necessary sensitivity to antibody levels in order to detect early localized Lyme Disease within the necessary window to treat with antibiotics and cure the disease.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  About 40% of those diagnosed with Lyme Disease present with symptoms that suggest a Late Dissemination Stage.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  This emphasized the need and importance of a new detection method for Lyme Disease in the early localized stage.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  New promising detection methods include a more direct way to test for the presence of <i>Borrelia burgdorferi</i>.
+===Current Research- New Detection Methods in Development===
+[[Image:graphic.jpeg|thumb|567px|right|Figure 5- A. Number of terL present based on number of <i>Borrelia burgdorferi</i> present in the spiked blood sample.  Reprinted from Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology. 2021;12. Available: https://www.frontiersin.org/article/10.3389/fmicb.2021.651217]]
-Stage 1- Early Localized Stage
+Successful treatment of Lyme Disease is dependent on early and accurate diagnosis.  However, with current methods, this is extremely rare and many go through suffering from symptoms and high costs before reaching an accurate diagnosis.  Even when they do reach a diagnosis, at this point their Lyme Disease is commonly in the latter two stages and treatment is less effective.
-Early localized Lyme DIsease occurs three days to one month after the initial tick bite.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref>  The local area of the bite will be the area that experiences the most symptoms.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref>  About 70% of individuals will develop a “bull’s eye” rash.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref><ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  This rash is characteristic of Lyme Disease and commonly leads to diagnosis.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref><ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  It may get as large as 15 cm and last up to three weeks if untreated.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref><ref name=lightpurple>[https://www.ncbi.nlm.nih.gov/books/NBK431066/#:~:text=Like%20syphilis%2C%20Lyme%20is%20classified,12%20months%20of%20the%20infection Skar GL, Simonsen KA. Lyme Disease. StatPearls. Treasure Island (FL): StatPearls Publishing; 2022. Available: http://www.ncbi.nlm.nih.gov/books/NBK431066/]</ref>  Symptoms at this stage include flu-like symptoms, such as fever, eye redness, neck stiffness, and headaches.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref><ref name=lightpurple>[https://www.ncbi.nlm.nih.gov/books/NBK431066/#:~:text=Like%20syphilis%2C%20Lyme%20is%20classified,12%20months%20of%20the%20infection Skar GL, Simonsen KA. Lyme Disease. StatPearls. Treasure Island (FL): StatPearls Publishing; 2022. Available: http://www.ncbi.nlm.nih.gov/books/NBK431066/]</ref>  Antibiotics at this stage are the most effective and can prevent further growth of Borrelia burgdorferi and sometimes lead to being cured of the disease.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref>
-Stage 2- Early Dissemination Stage
+Current research surrounding the early detection of Lyme Disease seems to be promising.  New detection methods are being developed through the detection of the multicopy terminase large subunit gene, <i>terL</i>.<ref name=orange>[https://www.frontiersin.org/articles/10.3389/fmicb.2021.651217/full Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.]</ref> TerL is found only in Lyme Disease causing bacteria, which is what makes it such an appealing target for detection of the disease.<ref name=orange>[https://www.frontiersin.org/articles/10.3389/fmicb.2021.651217/full Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.]</ref>  The gene <i>terL</i> encodes for the protein terL, which encodes for packing the genome and other essential factors for survival.<ref name=orange>[https://www.frontiersin.org/articles/10.3389/fmicb.2021.651217/full Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.]</ref>  Specifically, the terL homologs were found to be mainly present on the cp32 plasmid.<ref name=orange>[https://www.frontiersin.org/articles/10.3389/fmicb.2021.651217/full Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.]</ref>  Knowing which plasmid contains the highest concentration of the target protein allows for better detection targeting.<ref name=orange>[https://www.frontiersin.org/articles/10.3389/fmicb.2021.651217/full Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.]</ref>  Using terL, the current research group was able to detect even just one single <i>Borrelia burgdorferi</i> cell from a blood sample using PCR.<ref name=orange>[https://www.frontiersin.org/articles/10.3389/fmicb.2021.651217/full Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.]</ref>  This is unheard of because typically <i>Borrelia burgdorferi</i> needs time to replication and the new host needs time to develop antibodies to the disease.<ref name=orange>[https://www.frontiersin.org/articles/10.3389/fmicb.2021.651217/full Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.]</ref>
-The early dissemination stage of Lyme Disease occurs weeks to months after initial infection if left untreated.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref>  At this point, Borrelia burgdorferi begins to spread throughout the bloodstream and begins to affect other parts of the body beyond the initial bite site.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref>  General symptoms include fever, chills, fatigue, and lymphadenopathy.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref>  The heart may begin to be affected and lead to arrhythmias or myocarditis.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref>  About 4-8% of individuals experience cardiac symptoms.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  The musculoskeletal system may also be affected and lead to arthritis development.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref>  Arthritis is common with about 60% of those with Lyme Disease developing the symptom.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  Additionally, the nervous system may begin to be affected and present with loss of memory or facial paralysis.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref>  Neurological symptoms affect about 15-20% of individuals who are not treated.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>
-Stage 3- Late Dissemination Stage
+Specifically, <i>Borrelia burgdorferi</i> is released from the host's cells after interactions with stressors, such as antibiotics, which was shown previously, or spontaneously, just demonstrated.<ref name=orange>[https://www.frontiersin.org/articles/10.3389/fmicb.2021.651217/full Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.]</ref>  The research group aims to take advantage of the <i>Borrelia burgdorferi</i> leaving the cell in order to detect a more accurate number of <i>Borrelia burgdorferi</i> cells present in a host.<ref name=orange>[https://www.frontiersin.org/articles/10.3389/fmicb.2021.651217/full Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.]</ref>  The specific detection method is planning to utilize nine of the thirteen versions of terL that are found within the cp32 plasmid.<ref name=orange>[https://www.frontiersin.org/articles/10.3389/fmicb.2021.651217/full Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.]</ref>  By maximizing the number of primers and probes that target the protein, the sensitivity of detection will be greater.<ref name=orange>[https://www.frontiersin.org/articles/10.3389/fmicb.2021.651217/full Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.]</ref>
-Late disseminated Lyme Disease occurs after one year of initial infection and is also considered chronic Lyme Disease.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref>  Symptoms at this stage are long-term and may include encephalitis, meningitis, and severe arthritis.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref><ref name=lightpurple>[https://www.ncbi.nlm.nih.gov/books/NBK431066/#:~:text=Like%20syphilis%2C%20Lyme%20is%20classified,12%20months%20of%20the%20infection Skar GL, Simonsen KA. Lyme Disease. StatPearls. Treasure Island (FL): StatPearls Publishing; 2022. Available: http://www.ncbi.nlm.nih.gov/books/NBK431066/]</ref>  Arthritis at this point in the disease is commonly harsh on individuals' knees.<ref name=lightpurple>[https://www.ncbi.nlm.nih.gov/books/NBK431066/#:~:text=Like%20syphilis%2C%20Lyme%20is%20classified,12%20months%20of%20the%20infection Skar GL, Simonsen KA. Lyme Disease. StatPearls. Treasure Island (FL): StatPearls Publishing; 2022. Available: http://www.ncbi.nlm.nih.gov/books/NBK431066/]</ref>  Other symptoms from previous stages most likely would persist throughout this stage.<ref name=yellow7>{{cite book|last1=Tortora|first1=Gerard J.|last2=Funke|first2=Berdell R.|last3=Case|first3=Christine L.|title=Microbiology: An Introduction|date=2013|publisher=Pearson Education, Inc.|location=United States of America|isbn=978-0-321-73360-3|pages=658–659}}</ref>
-<br><b>INSERT IMAGE OF BULLS EYE</b>
+In order to determine the ability of this new detection method, the research group examined terL presence after qPCR in <i>Borrelia burgdorferi</i> spiked blood samples.<ref name=orange>[https://www.frontiersin.org/articles/10.3389/fmicb.2021.651217/full Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.]</ref>  As can be seen in Figure 5A, the greater number of <i>Borrelia burgdorferi</i> present in the spiked blood sample, the greater number of terL copies were observed.<ref name=orange>[https://www.frontiersin.org/articles/10.3389/fmicb.2021.651217/full Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.]</ref>  Additionally, in Figure 5B, a linear relationship was found between the amount of <i>Borrelia burgdorferi</i> present in the spiked blood sample and the intensity of terL signals.
-==Evasion and Detection==
+This research group is currently working towards clinical trials for utilizing this new detection method of Lyme Disease.<ref name=orange>[https://www.frontiersin.org/articles/10.3389/fmicb.2021.651217/full Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3 Shan J, Jia Y, Teulières L, Patel F, Clokie MRJ. Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood. Frontiers in Microbiology.]</ref>  The new method revolutionizes Lyme Disease diagnosis and may allow for thousands of individuals to be diagnosed within the early localized stage of Lyme Disease and seek treatment before great suffering.
 ==Treatment==
-When diagnosed early enough, Lyme Disease is treatable and curable.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  Diagnoses that fall within the early stage of the disease is deemed most likely to be curable.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  The antibiotics amoxicillin and doxycycline are commonly used to treat early detection and have not yet developed neurological symptoms.<ref name=brightgreen>[https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research Lyme Disease Antibiotic Treatment Research | NIH: National Institute of Allergy and Infectious Diseases. [cited 18 Apr 2022]. Available: https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research
+When diagnosed early enough, Lyme Disease is treatable and curable.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  Diagnoses that fall within the early stage of the disease is deemed most likely to be curable.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  The antibiotics amoxicillin and doxycycline are commonly used to treat early detection and have not yet developed neurological symptoms.<ref name=brightgreen>[https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research NIH. Lyme Disease Antibiotic Treatment Research | NIH: National Institute of Allergy and Infectious Diseases. 2018 [cited 18 Apr 2022]. Available: https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research]</ref>A course of antibiotics is recommended to last 14 to 28 days depending on the medication, dosage, and individual.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  For those with arthritis, which indicates late stages of Lyme Disease, a course of the aforementioned for 28 days is recommended.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Individuals with neurological symptoms are recommended to have treatment via intravenous ceftriaxone.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>
-]</ref> A course of antibiotics is recommended to last 14 to 28 days depending on the medication, dosage, and individual.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  For those with arthritis, which indicates late stages of Lyme Disease, a course of the aforementioned for 28 days is recommended.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Individuals with neurological symptoms are recommended to have treatment via intravenous ceftriaxone.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>
-If an individual has been previously infected with Borrelia burgdorferi and developed Lyme Disease it is possible to become infected again.<ref name=darkpurple>[https://www.uptodate.com/contents/lyme-disease-treatment-beyond-the-basics]</ref>   Those who were infected with late Lyme Disease are very unlikely to become reinfected with Lyme Disease again.<ref name=darkpurple>[https://www.uptodate.com/contents/lyme-disease-treatment-beyond-the-basics]</ref>  Their bodies have developed a stronger and longer-lasting immune response via antibodies to the disease.<ref name=darkpurple>[https://www.uptodate.com/contents/lyme-disease-treatment-beyond-the-basics]</ref>  However, those who were treated and cured of Lyme Disease in the early stages may be able to become infected again.<ref name=darkpurple>[https://www.uptodate.com/contents/lyme-disease-treatment-beyond-the-basics]</ref>  This time an individual's body would most likely still have antibodies in your bloodstream, making your infection more difficult to diagnose because.<ref name=darkpurple>[https://www.uptodate.com/contents/lyme-disease-treatment-beyond-the-basics]</ref>  Common detection methods today, as mentioned above, only can detect Borrelia burgdorferi, not an active infection vs an inactive infection.<ref name=darkpurple>[https://www.uptodate.com/contents/lyme-disease-treatment-beyond-the-basics]</ref>  The most likely way to diagnose Lyme Disease again would be the appearance of a bull’s eye.<ref name=darkpurple>[https://www.uptodate.com/contents/lyme-disease-treatment-beyond-the-basics]</ref>
+If an individual has been previously infected with <i>Borrelia burgdorferi</i> and developed Lyme Disease it is possible to become infected again.<ref name=darkpurple>[https://www.uptodate.com/contents/lyme-disease-treatment-beyond-the-basics Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43:1089.]</ref>   Those who were infected with late Lyme Disease are very unlikely to become reinfected with Lyme Disease again.<ref name=darkpurple>[https://www.uptodate.com/contents/lyme-disease-treatment-beyond-the-basics Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43:1089.]</ref>  Their bodies have developed a stronger and longer-lasting immune response via antibodies to the disease.<ref name=darkpurple>[https://www.uptodate.com/contents/lyme-disease-treatment-beyond-the-basics Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43:1089.]</ref>  However, those who were treated and cured of Lyme Disease in the early stages may be able to become infected again.<ref name=darkpurple>[https://www.uptodate.com/contents/lyme-disease-treatment-beyond-the-basics Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43:1089.]</ref>  This time an individual's body would most likely still have antibodies in your bloodstream, making your infection more difficult to diagnose because.<ref name=darkpurple>[https://www.uptodate.com/contents/lyme-disease-treatment-beyond-the-basics Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43:1089.]</ref>  Common detection methods today, as mentioned above, only can detect <i>Borrelia burgdorferi</i>, not an active infection vs an inactive infection.<ref name=darkpurple>[https://www.uptodate.com/contents/lyme-disease-treatment-beyond-the-basics Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43:1089.]</ref>  The most likely way to diagnose Lyme Disease again would be the appearance of a bull’s eye.<ref name=darkpurple>[https://www.uptodate.com/contents/lyme-disease-treatment-beyond-the-basics Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43:1089.]</ref>
-Unfortunately, it has been found that for those with post-treatment Lyme disease syndrome (PTLDS) no antibiotic treatment is recommended.https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research  Previous work has found that some fatigue can be improved with antibiotic treatment for PTLDS individuals.https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research  Another study found no improvement with antibiotic treatment in PTLDS individuals.https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research  Thus, the overall quality of life does not increase enough that it is recommended to undergo a course of antibiotics for those with PTLDS.https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research
+Unfortunately, it has been found that for those with post-treatment Lyme disease syndrome (PTLDS) no antibiotic treatment is recommended.<ref name=brightgreen>[https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research NIH. Lyme Disease Antibiotic Treatment Research | NIH: National Institute of Allergy and Infectious Diseases. 2018 [cited 18 Apr 2022]. Available: https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research]</ref> Previous work has found that some fatigue can be improved with antibiotic treatment for PTLDS individuals.<ref name=brightgreen>[https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research NIH. Lyme Disease Antibiotic Treatment Research | NIH: National Institute of Allergy and Infectious Diseases. 2018 [cited 18 Apr 2022]. Available: https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research]</ref>  Another study found no improvement with antibiotic treatment in PTLDS individuals.<ref name=brightgreen>[https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research NIH. Lyme Disease Antibiotic Treatment Research | NIH: National Institute of Allergy and Infectious Diseases. 2018 [cited 18 Apr 2022]. Available: https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research]</ref>  Thus, the overall quality of life does not increase enough that it is recommended to undergo a course of antibiotics for those with PTLDS.<ref name=brightgreen>[https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research NIH. Lyme Disease Antibiotic Treatment Research | NIH: National Institute of Allergy and Infectious Diseases. 2018 [cited 18 Apr 2022]. Available: https://www.niaid.nih.gov/diseases-conditions/lyme-disease-antibiotic-treatment-research]</ref>
-There are a few treatments in the process of discovery.  The use of vancomycin is being examined as it has been shown to almost completely destroy Borrelia burgdorferi in vitro during the stationary phase of the spirochetes.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Vancomycin seems to target the susceptible cell wall synthesis inhibitors in order to destroy Borrelia burgdorferi.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Another group is examining the combination of a few drugs in vitro and currently in mouse models.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  They are investigating the combination of Doxycycline, which is currently used to treat early Lyme Disease, Cefoperazone, and Daptomycin.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>
+There are a few treatments in the process of discovery.  The use of vancomycin is being examined as it has been shown to almost completely destroy <i>Borrelia burgdorferi</i> in vitro during the stationary phase of the spirochetes.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Vancomycin seems to target the susceptible cell wall synthesis inhibitors in order to destroy <i>Borrelia burgdorferi</i>.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Another group is examining the combination of a few drugs in vitro and currently in mouse models.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  They are investigating the combination of Doxycycline, which is currently used to treat early Lyme Disease, Cefoperazone, and Daptomycin.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>
 ==Prevention==
-One of the best mechanisms for treating Lyme Disease is not getting it to begin with.  There are many precautionary steps that can be taken in order to avoid being bitten by an infected tick.
+[[File:sign.jpeg|thumb|300px|left|Figure 6- Prevention methods promoted in order for individuals to avoid becoming infected with <i>Borrelia burgdorferi</i> from ticks and getting Lyme Disease. https://www.cdc.gov/ncezid/dvbd/media/lymedisease.html]]
-Methods of prevention include various factors that help diminish the disease risk.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref> Lyme Disease control methods commonly fall under two categories, the ecological approach, and the human behavior approach.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>
-Ecological approaches focus on the vector for the disease itself, the tick, and its transmission.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Some suggestions in order to decrease disease risk include reduction of ticks, Lyme Disease hosts (such as white-footed mice or squirrels), and reduction of transmission from hosts to ticks.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Any long-term plan to prevent Lyme disease from an ecological approach must take climate change into consideration because as the temperatures increase the locations in which the tick populations and Borrelia burgdorferi can survive will expand.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Additional methods of Lyme Disease prevention that have been suggested include, mass culling of white-tailed deer or white-footed mice, as they are both reservoirs for the disease.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  However, a mass culling has been found to only be effective in isolated populations where Lyme Disease can be completely eliminated.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Even if one reservoir is left with the disease in a population, it will spread again.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Thus, mass cullings are not seen as a viable option.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>
+One of the best mechanisms for treating Lyme Disease is not getting it to begin with.  There are many precautionary steps that can be taken in order to avoid being bitten by an infected tick.  Methods of prevention include various factors that help diminish the disease risk.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref> Lyme Disease control methods commonly fall under two categories, the ecological approach, and the human behavior approach.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref> Ecological approaches focus on the vector for the disease itself, the tick, and its transmission.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Some suggestions in order to decrease disease risk include reduction of ticks, Lyme Disease hosts (such as white-footed mice or squirrels), and reduction of transmission from hosts to ticks.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Any long-term plan to prevent Lyme disease from an ecological approach must take climate change into consideration because as the temperatures increase the locations in which the tick populations and <i>Borrelia burgdorferi</i> can survive will expand.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Additional methods of Lyme Disease prevention that have been suggested include, mass culling of white-tailed deer or white-footed mice, as they are both reservoirs for the disease.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  However, a mass culling has been found to only be effective in isolated populations where Lyme Disease can be completely eliminated.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Even if one reservoir is left with the disease in a population, it will spread again.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Thus, mass cullings are not seen as a viable option.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>
-The human behavior approach focuses on human behaviors that influence disease risk.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  Some suggestions include walking closer to the center of paths in order to avoid bushes, wearing long clothes that cover bare skin, wearing bug spray, if possible modifying the environment, checking for ticks after outdoor activities or daily, and if ticks are found on you properly removing them promptly in order to avoid transmission of Borrelia Burgdorferi.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>
+The human behavior approach focuses on human behaviors that influence disease risk.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  Some suggestions include walking closer to the center of paths in order to avoid bushes, wearing long clothes that cover bare skin, wearing bug spray, if possible modifying the environment, checking for ticks after outdoor activities or daily, and if ticks are found on you properly removing them promptly in order to avoid transmission of <i>Borrelia burgdorferi</i>.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>
-If one is bitten by a tick and fits the following criteria then antibiotic treatment may be helpful in taking precautionary measures to avoid Borrelia Burgdorferi transmission:  1. Incidence of Borrelia burgdorferi infection, or Lyme Disease, is at least 20% of an individual's area, 2. The tick has been attached for at least 36 hours, 3. Antibiotics can be started within 72 hours of removal of the tick.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  If individuals do not fit this criterion then antibiotic treatment as a method of prevention is not suggested.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  Those who have been bitten by a tick should not get tested for Lyme Disease right away and should be monitored for symptoms closely for 30 days.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  As of today, it is not suggested to get tested right away for Lyme Disease because it takes time for the human body to produce antibodies to the disease.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  After the 30-day period of time, if experiencing symptoms, individuals may be tested for Lyme Disease as their body would have produced some antibodies by this time.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>
+If one is bitten by a tick and fits the following criteria then antibiotic treatment may be helpful in taking precautionary measures to avoid <i>Borrelia burgdorferi</i> transmission:  1. Incidence of <i>Borrelia burgdorferi</i> infection, or Lyme Disease, is at least 20% of an individual's area, 2. The tick has been attached for at least 36 hours, 3. Antibiotics can be started within 72 hours of removal of the tick.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  If individuals do not fit this criterion then antibiotic treatment as a method of prevention is not suggested.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  Those who have been bitten by a tick should not get tested for Lyme Disease right away and should be monitored for symptoms closely for 30 days.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>  As of today, it is not suggested to get tested right away for Lyme Disease because it takes time for the human body to produce antibodies to the disease.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  After the 30-day period of time, if experiencing symptoms, individuals may be tested for Lyme Disease as their body would have produced some antibodies by this time.<ref name=navy>[https://pubmed.ncbi.nlm.nih.gov/20425509/ Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10: 13–20. doi:10.1007/s11882-009-0077-3]</ref>
 ==Vaccines==
-Two Lyme Disease vaccines have been created and one of which was placed on the market temporarily; however, there are currently no Lyme Disease vaccines on the market.  Previous vaccines include LYMErix and ImuLyme.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Both of these vaccines utilized the outer membrane protein OspA.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  The vaccines protect individuals from Lyme Disease by vaccinating against the OspA protein.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  As a result of this, those vaccinated would then develop anti-OspA antibodies which would bind and neutralize Borrelia burgdorferi that was transmitted from the tick.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  The Borrelia burgdorferi would not be able to penetrate the skin, thus not infecting an individual.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>
+Two Lyme Disease vaccines have been created and one of which was placed on the market temporarily; however, there are currently no Lyme Disease vaccines on the market.  Previous vaccines include LYMErix and ImuLyme.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Both of these vaccines utilized the outer membrane protein OspA.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  The vaccines protect individuals from Lyme Disease by vaccinating against the OspA protein.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  As a result of this, those vaccinated would then develop anti-OspA antibodies which would bind and neutralize <i>Borrelia burgdorferi</i> that was transmitted from the tick.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  The <i>Borrelia burgdorferi</i> would not be able to penetrate the skin, thus not infecting an individual.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>
 The first vaccine, LYMErix, was created and placed on the market in December of 1998.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref> It was found that with two doses there was a 49% efficacy rate and with three doses a 76% efficacy rate.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref> The three doses must be given over a one-year period of time, and the vaccine is not considered effective until after all three doses.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Thus, people may not be considered safe until after all three doses.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>
-Despite the vaccine being safe and somewhat effective, LYMErix was taken off the market.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  LYMErix was removed in 2002 from the market and after stage three clinical trials in 1998.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  LYMErix was removed from the market due to low demand.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  This was a result of the vaccine only being marketed to people with high-risk jobs, instead of to the general public as precautionary measures.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Additionally, Borrelia burgdorferi’s geographical location is limited thus limiting the number of individuals within the market for the vaccine.<<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Other issues with LYMErix included only having a 76% affection rating, which the FDA deemed as inefficient in preventing Lyme Disease.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Additionally, human clinical trials for the vaccine did not include anyone below the age of 15, which is a group that is considered at higher risk for Lyme Disease.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Controversy also surrounded the company as the vaccine was suspected to cause arthritis.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  This claim was dismissed after an investigation by the FDA in 1998.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  However, the controversies remained present within conversations surrounding LYMErix.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>
+Despite the vaccine being safe and somewhat effective, LYMErix was taken off the market.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  LYMErix was removed in 2002 from the market and after stage three clinical trials in 1998.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  LYMErix was removed from the market due to low demand.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  This was a result of the vaccine only being marketed to people with high-risk jobs, instead of to the general public as precautionary measures.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Additionally, <i>Borrelia burgdorferi</i>’s geographical location is limited thus limiting the number of individuals within the market for the vaccine.<<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Other issues with LYMErix included only having a 76% affection rating, which the FDA deemed as inefficient in preventing Lyme Disease.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Additionally, human clinical trials for the vaccine did not include anyone below the age of 15, which is a group that is considered at higher risk for Lyme Disease.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Controversy also surrounded the company as the vaccine was suspected to cause arthritis.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  This claim was dismissed after an investigation by the FDA in 1998.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  However, the controversies remained present within conversations surrounding LYMErix.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>
 ImuLyme was developed in 1998 however never made it to the market for public use.<ref name=lightgray>[https://sites.newpaltz.edu/ticktalk/ottaway-2014-lyme-disease-investigation/history-behind-the-first-lyme-disease-vaccine/#:~:text=Pasteur%20Merieux%20Connaught's%20Lyme%20vaccine,Inquirer%20article%20published%20in%201998 Nesich H. The History Behind the First Lyme Disease Vaccine – Tick Talk. [cited 18 Apr 2022]. Available: https://sites.newpaltz.edu/ticktalk/ottaway-2014-lyme-disease-investigation/history-behind-the-first-lyme-disease-vaccine/]</ref>  Two to three doses were necessary for the vaccine to be deemed effective.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  However, the controversies remained present within conversations surrounding LYMErix.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  With two doses 68% efficacy was found and with three doses 92% efficacy was found.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  The efficacy was higher than LYMErix likely due to its difference in composition.<ref name=lightpink>[https://www.nature.com/articles/s41541-022-00429-5 Dattwyler RJ, Gomes-Solecki M. The year that shaped the outcome of the OspA vaccine for human Lyme disease. npj Vaccines. 2022;7: 1–5. doi:10.1038/s41541-022-00429-5]</ref>  ImuLyme has a chemical composition of purified lipoproteins, which serve as important proteins within the disease.<ref name=lightpink>[https://www.nature.com/articles/s41541-022-00429-5 Dattwyler RJ, Gomes-Solecki M. The year that shaped the outcome of the OspA vaccine for human Lyme disease. npj Vaccines. 2022;7: 1–5. doi:10.1038/s41541-022-00429-5]</ref>  The purified proteins did not need to absorb the adjuvant, thus allowing it to be overall more effective.<ref name=lightpink>[https://www.nature.com/articles/s41541-022-00429-5 Dattwyler RJ, Gomes-Solecki M. The year that shaped the outcome of the OspA vaccine for human Lyme disease. npj Vaccines. 2022;7: 1–5. doi:10.1038/s41541-022-00429-5]</ref>
@@ Line 91: / Line 108: @@
 ImuLyme never made it to the market because the company decided to not produce the vaccine by not pursuing licensure.<ref name=lightpink>[https://www.nature.com/articles/s41541-022-00429-5 Dattwyler RJ, Gomes-Solecki M. The year that shaped the outcome of the OspA vaccine for human Lyme disease. npj Vaccines. 2022;7: 1–5. doi:10.1038/s41541-022-00429-5]</ref>  Their vaccine was set to hit the market at the same time as LYMErix was and the manufacturers of ImuLyme understood that there was not a large enough demand in the market for them both.<ref name=lightpink>[https://www.nature.com/articles/s41541-022-00429-5 Dattwyler RJ, Gomes-Solecki M. The year that shaped the outcome of the OspA vaccine for human Lyme disease. npj Vaccines. 2022;7: 1–5. doi:10.1038/s41541-022-00429-5]</ref>  The profit was seen as too small, thus the vaccine was never produced.<ref name=lightpink>[https://www.nature.com/articles/s41541-022-00429-5 Dattwyler RJ, Gomes-Solecki M. The year that shaped the outcome of the OspA vaccine for human Lyme disease. npj Vaccines. 2022;7: 1–5. doi:10.1038/s41541-022-00429-5]</ref>  Additionally, the vaccine was found to be not as effective in those over the age of 60, which was another age group at high risk of contracting Lyme Disease.<<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>
-Potential future vaccines should take multiple things into consideration in order to be deemed effective and avoid previous vaccine flaws.  Due to the nature of the outer surface proteins rapidly changing, it is difficult to target Borrelia burgdorferi and destroy it.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  In order to effectively target Borrelia burgdorferi, a potential vaccine needs to find a protein that is continuously expressed.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  OspA, outer surface protein A, does just this.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Given that it is expressed throughout all stages of the tick during potential transmission, it fits the criteria for a protein to target with a vaccine.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  This is the same outer surface protein that was targeted in the previous vaccines.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  While the vaccines worked, they were not as effective as the market would have liked.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Thus, future vaccines need to keep in mind these previous vaccine engineering flaws in order to make a new vaccine that is effective.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  However, the new vaccine would be difficult to properly engineer because OspA is only continuously expressed in the tick midgut.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Therefore, the anti-OspA antibodies would need to travel to the midgut in order to destroy the bacteria before traveling to the salary glands of the tick to transmit Borrelia burgdorferi.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Additionally, criteria for a future vaccine from a marketing value perspective include both private and public business coordination to develop the vaccine from a public health standpoint and educate individuals that the components of the vaccine are safe.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>
+Potential future vaccines should take multiple things into consideration in order to be deemed effective and avoid previous vaccine flaws.  Due to the nature of the outer surface proteins rapidly changing, it is difficult to target <i>Borrelia burgdorferi</i> and destroy it.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  In order to effectively target <i>Borrelia burgdorferi</i>, a potential vaccine needs to find a protein that is continuously expressed.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  OspA, outer surface protein A, does just this.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Given that it is expressed throughout all stages of the tick during potential transmission, it fits the criteria for a protein to target with a vaccine.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  This is the same outer surface protein that was targeted in the previous vaccines.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  While the vaccines worked, they were not as effective as the market would have liked.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Thus, future vaccines need to keep in mind these previous vaccine engineering flaws in order to make a new vaccine that is effective.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  However, the new vaccine would be difficult to properly engineer because OspA is only continuously expressed in the tick midgut.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Therefore, the anti-OspA antibodies would need to travel to the midgut in order to destroy the bacteria before traveling to the salary glands of the tick to transmit <i>Borrelia burgdorferi</i>.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>  Additionally, criteria for a future vaccine from a marketing value perspective include both private and public business coordination to develop the vaccine from a public health standpoint and educate individuals that the components of the vaccine are safe.<ref name=purple>[https://academic.oup.com/cid/article/52/suppl_3/s253/444754 Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn? Clinical Infectious Diseases. 2011;52: s253–s258. doi:10.1093/cid/ciq116]</ref>
 There are currently multiple vaccines in development.  These new vaccines are attempting to address the hardships of the previous vaccines, including the efficacy and genetic diversity of Borrelia species.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  One vaccine, VLA15, is using six different recombinant OspA proteins in order to target as many spirochetes as possible.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  VLA15 is the only vaccine currently in human clinical trials.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Another vaccine is combining antigens from different stages of infection of Borrelia.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  This is aimed to target Borrelia that is not killed within the tick midgut or blocked from exiting.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Perhaps the most interesting vaccine currently in the works is not specifically an anti-Borrelia vaccine but rather an anti-tick vaccine.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  An anti-tick vaccine is seen as a precautionary step for many tick-borne illnesses.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  Ixodes ticks specifically are known to cause 16 human pathogens.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>  With this anti-tick vaccine, individuals could be protected against all 16 pathogens.<ref name=pink>[https://www.frontiersin.org/articles/10.3389/fmed.2021.666554/full Bobe JR, Jutras BL, Horn EJ, Embers ME, Bailey A, Moritz RL, et al. Recent Progress in Lyme Disease and Remaining Challenges. Frontiers in Medicine. 2021;8. Available: https://www.frontiersin.org/article/10.3389/fmed.2021.666554]</ref>
 ==Conclusion==
+While previous and current methods for Lyme Disease detection exist, there is a need for current research to expand and put forward a new detection method.  Early detection of Lyme Disease is crucial to treating and curing the disease.  <i>Borrelia burgdorferi</i>'s evasion mechanisms lead to difficulty in developing new methods for detection.  Overall, while work exists surrounding <i>Borrelia burgdorferi</i> and Lyme Disease, further investigation is necessary in order to help elevate those lives who are greatly impacted by the disease.
 ==References==
 <references/>
 <br><br>Authored for BIOL 238 Microbiology, taught by [mailto:slonczewski@kenyon.edu Joan Slonczewski], 2022, [http://www.kenyon.edu/index.xml Kenyon College]