Yersinia Pestis (Pathogenesis)

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University of Oklahoma Study Abroad Microbiology in Arezzo, Italy[1]

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Scanning electron microscope image of Clostridium difficile. From: Bioquell.com [2]

Etiology/Bacteriology

Taxonomy

| Domain = Bacteria | Phylum = Firmicutes | Class = Clostridia | Order = Clostridiales | Family = Clostridiaceae | Genus = Clostridium | species = C. difficile

Pathogenesis

Transmission

Fleas

Y. pestis is most commonly transmitted to humans through the bites of infected fleas, resulting in either primary bubonic plague or septicemic plague (1). In the midgut of its principal flea vector (Xenopsylla cheopis), Y. pestis survives cytotoxic digestion of blood plasma through the action of Yersinia murine toxin (Ymt) (2). Ymt is a plasmid-encoded phospholipase D (PLD) (2). Through the action of this PLD, Y. pestis is able to colonize the flea midgut, which may have caused the bacterium to obligately transmit to arthropods (2). The hemin storage system locus (hms) also contributes to the pathogenicity of Y. pestis in fleas (3). Y. pestis hms encodes for a storage system that synthesizes extracellular saccharides in order to facilitate colonization of the proventriculus in the foregut (3). The formation of biofilms in the proventriculus contributes to the transmission of the plague in fleas (3).

Fluid/Tissue

Y. pestis can be transmitted to humans through the handling of fluids or tissue from infected animals (1). Once Y. pestis has entered the human host, the bacterium spreads throughout the lymphatic system and enters the bloodstream within 2-6 days (4). The spread of Y. pestis throughout the lymphatic system triggers a large-scale immune response with the appearance of buboes on the armpits, groin, and neck (5). Increased numbers of bacteria in the bloodstream promotes the odds of human-human transmission (6). Contact with contaminated fluid or tissue typically results in bubonic plague or septicemic plague (1).

Infectious Droplets

Y. pestis can also be transmitted through the air via infectious droplets from coughing (1). Transmission of infectious droplets is the only method of spreading the plague from person to person (1). Transmission of infectious droplets through coughing enables Y. pestis to colonize the lungs (5). This type of infection is called “pneumonic plague” and has a mortality rate close to 100 percent (1,5).

Clinical features

Symptoms

The symptoms of Yersinia Pestis presents in different ways, but the three most common are bubonic, septicemic, and pneumonic plague. [1]

Bubonic Plague

This type of plague usually results from the bite of an infected flea. Once infection sets, the patient has sudden onset of fever, headache, chills, weakness, and the development of swollen nodes known as buboes, where isolated bacteria multiply and grow. If not treated the bacteria can spread to other areas [1] .

Septicemic Plague

This type of plague can either develop primarily or as a result from untreated bubonic plague. Symptoms from this include bleeding into the skin and other organs ranging to tissue blackening and death, especially in the fingers, toes, and the nose. [1]

Pneumonic Plague

This type of plague either develops from inhaling infectious droplets or from untreated bubonic/septicemic plague and bacteria spreading to the lungs. At this point the plague is infectious and can be spread from person to person by infectious droplets. Symptoms from this type of plague include fever, headache, weakness, and a developing pneumonia that heightens symptoms of cough, chest pain and shortness of breath. [1]

Morbidity and Mortality

Worldwide, the number of cases reported to the World Health Organization range between 1000 and 2000 per year. However, according to WHO, the real number is likely much higher. Because of this, it is difficult to assess mortality rate, especially in developing countries with poor diagnostics and under reporting. The mortality rate cited by WHO, is between 8-10%, but again, the predicted percentage is expected to be much higher. [2]

Treatment

Antibiotics

Individuals suspected of infection from Yesinia pestis should be immediately admitted to hospitals for isolation and proper management. A number of powerful antibiotics are used to treat the illness, with streptomycin usually prescribed as the primary drug of choice. Other possible antibiotics include gentamicin, chloramphenicol, tetracyclines, and fluoroquinolones. The antibiotic levofloxacin has also been recently approved by the Food and Drug Administration as appropriate treatment. Antibiotic dosages are typically administered for the full period of ten days or for three days after the fever has subsided. However, the selection of antibiotic therapy is crucial, as several classes of antibiotics have proven to be ineffective in treatment for the plague. These include penicillins, cephalosporins, and macrolides.

Prophylaxis

Prophylactic therapy is a common mode of treatment for individuals who have been exposed to potentially infected individuals. Patients with possible exposure to Y. pestis should be administered antibiotics if the exposure occurred within the span of six days as a means of preventative therapy.

The usage of prophylactic therapy may also be used as a preventative measure for individuals who must be, for short periods of time, involved in circumstances where the potential of infection may be unavoidable.

Prevention

Yersinia pestis can be transmitted to humans from the bites of inflected fleas or handling of plague-infected tissues. In the case of plague pneumonia, transmission can occur via inhalation of the cough droplets from another infected individual. While no available vaccine currently exists, several effective means of prevention are to diminish the possibility of rodent infestation around homes by clearing away cluttered debris within the vicinity and to apply flea control products for pets that roam freely in the open. The application of insect repellent for individuals in outdoor areas is an effective measure for protection against flea bites. Any contact with potentially infected animals should be limited, and the usage of gloves as a barrier against possible transmission should be utilized when necessary.

Means of prevention can also be applied in hospital settings where the possibility of transmission can be high. Standardized procedures of handwashing and utilization of gowns, latex gloves, and protective devices should be followed to protect all body orifices from coming into contact with Y. pestis. Restrictions of patients suspected with plague should be enacted to prevent the spread of disease to other individuals. This includes isolated treatment of infected patient as well as the inhibition of movement of the patient outside of the isolation room until the infection ceases to exist.

Host Immune Response

The host innate immune response involves macrophages, inflammation, and the activation of the complement cascade. However, Yersinia Pestis has evolved different mechanisms for evading this immune response, both in the innate and adaptive immune response.[3]

Attack on Innate Immune Response

Most of Y. pestis are killed off by encounter with neutrophils and many that survive manage are a special subtype (facultative Y. pestis). Using the macrophages, they are then able to proliferate and express different virulence factors, before the spread systemically throughout the body. In addition, the LPS (lipopolysaccharide) structure in this organism allows the bacteria to become resistant to serum-mediated lysis during its transition from its flea vector to animal host. The bacteria coming from the macrophages, therefore, are resistant to phagocytosis and can inhibit the production of proinflammatory cytokines, which in turn attenuates the adaptive immune response of the host. Yet another immune response that is affected is the complement pathways. The complement cascade of the innate immune response (which is initiated by macrophages binding to foreign antigen) has three different effector functions: opsonization, which leads to phagocytosis, inflammation, and the formation of a membrane-attack complex, which leads to direct killing. However, Y. pestis has developed a resistance to complement-mediated lysis in an effort to survive transmission between flea and animal. In addition, during replication within a macrophage, the bacteria form a needle-like complex that (once released from the macrophage), they use to inject six different effector proteins into different cells to further inhibit the immune response. Targets for this injection include macrophages, dendritic cells, and neutrophils. Besides paralyzing these phagocytic cells, these proteins also target the proinflammatory recruitment response initiated by infected cells. Finally, these proteins also targeting NK cells, which further inhibit the innate immune response. [3]

Attack on Adaptive Immune Response

Because the innate immune response has been so severely affected, the adaptive immune system cannot be properly initiated. Dendritic cells (which are the cells that link between the innate and adaptive immune response) are targeted early on, and as a result the activation of the adaptive immune response is hindered because dendritic cells cannot mature and start T-cell mediated immune response. Because of this, the humoral response (B-cell response) cannot be properly triggered.[1]

Host Immune Response

In order to combat the Y. pestis infection, the host cell must reactivate its specific humoral and cellular response mechanisms to establish a protective immunity. This involves neutralizing virulence factors and delivering antibody/antigen complexes to B cells, macrophages, and dendritic cells (which promotes T-cell activation).[3] Often times, this activation is a result of the very pathology of the organism. Although the bacterium attenuates the inflammatory response and causes apoptosis of naïve macrophages, activated macrophages are killed by a process known as pyroptosis. Interestingly, this process has the opposite effect and activates the previously attenuated inflammatory response, and benefits the host further by accelerating and amplifying this response to combat the bacterial infection and stimulate proper immune response pathways. Hyper-inflammation, however can result in tissue damage and organ malfunction.[4]

References

1. "Plague Symptoms." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 25 July 2012. Web. 16 July 2014. [<http://www.cdc.gov/plague/symptoms/index.html>]
2. "Plague-frequently asked questions." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 25 July 2012. Web. 16 July 2014. [<http://www.cdc.gov/plague/faq/>.]
3. D'elios, Mario Milco. "Role of immune response in Yersinia pestis infection." The Journal of Infection in Developing Countries: n. pag. Web. 16 July 2014. [<www.jidc.org/index.php/journal/article/download/21918303/599>]
4. "Innate immune response during Yersinia infection: critical modulation of cell death mechanisms through phagocyte activation." Innate immune response during Yersinia infection: critical modulation of cell death mechanisms through phagocyte activation. N.p., 1 Sept. 2009. Web. 16 July 2014. [<http://www.jleukbio.org/content/86/5/1153.full>]

Created by {Krishna Manohar, Michael Grassi, Christina Cheng, Johnson Ong}, students of Tyrrell Conway at the University of Oklahoma.