Leptospirosis induced by L. borgpetersenii
- 1 Etiology/Bacteriology
- 2 Pathogenesis
- 3 Clinical Features
Although there are seven causative agents of the most widespread zoonosis and emerging public health issue, Leptospirosis, one in particular called Leptospira borgpetersenii cannot live outside of the host because it is evolving toward dependence on a strict host-to-host transmission cycle . The leptospires that cause this deadly zoonosis are approximately 6—20 micrometers in length, and they are thin, motile spirochetes. What is especially unique about these spirochetes is that they feature surface structures of both Gram-positive and Gram-negative bacteria. The Gram-negative structure includes a double-membrane and the presence of LPS, but the Gram-positive structure is characterized by a close association of the murein wall with the cytoplasmic membrane . There is a broad distribution for this deadly zoonosis across tropical, subtropical, and temperate regions that concentrate in developing countries . Although many of the mechanisms of pathogenesis are still undergoing research, potential virulence factors have been identified using many genetic manipulations of this bacteria for control and prevention. Two strains of L. borgpetersenii serovar Hardjo have been found to have distinct phenotypes and virulence, L550 and and JB197 . Half a million cases are reported yearly, and there is a mortality rate ranging from 5-10% for severe infections .
Out of all of the causative agents of leptospirosis, L. borgpetersenii has limited transmission potential. L. borgpetersenii uses a host-to-host transmission cycle that it has gradually gained dependence on through its evolution . Leptospirosis is known to be spread through the contact with water. The disease is caused in humans either through direct contact with infected animals or through contact with urine of an infected animal within the environment.
Studies claim that oral-fecal transmission is the primary mode of host-to-host transmission for L. borgpetersenii due to the consumption of milk by infected dairy cows in one particular study, but there is another hypothesis that states that infected rats were the cause of the transmission to humans. In fact, rats seem to be the most common carriers when analyzing results of most studies .
Gene Regulation and Environment Adaptation
One hypothesis states that L. borgpetersenii is not able to adapt to external environments due to its gene regulation. . Evidence indicates that the cognate regulatory factors that are encoded by anti- σ factor antagonist and σ factor regulator are dispersed through the genome as opposed to being cotranscribed with the ECF, which is unique compared to other causative agents of this deadly zoonosis. Using the comparisons between different causative agents, researchers have developed hypotheses as to why this particular pathogen cannot live outside of its host. L. interrogans, another causative agent of Leptospirosis that can adapt to external environments, has 24 response regulator-histidine kinase pairs, but L. borgpetersenii only has 18 two-component response regulators. L. borgpetersenii also has half of the response regulators of L. interrogans as well. Despite all of this, L. borgpetersenii has been found to have two vital transcriptional regulators for mammalian host survival: Fur the iron response regulator, and HcrA, a regulator of thermal stress. .
Infectious Dose and Incubation Period
The incubation period was found to be 2—20 days, but the infectious dose has not yet been determined. The optimal temperature for L. borgpetersenii was found to be between a range of 28-30 degrees Celsius, and the optimal pH was found to be 7.2—7.4 in reported cases and studies .
Leptospirosis was reinstated as a nationally notifiable disease in January 2013. There were approximately 100-200 cases identified in the U.S. annually, and 50% of these cases are found to be in Hawaii. 775 people were exposed to the disease in 1998, the largest recorded U.S. outbreak , but only 110 were infected. More cases have been reported in Peru and Ecuador after a flood in 1998. Thailand also reported more cases between 1995—2000. There were two cases found in Thailand by travelers who had walked in flood water prior to hospitalization that were diagnosed with Leptospirosis induced by L. borgpetersenii. The mortality rate for this disease has been reported to be between a range of 5—10%. Large outbreaks seem to occur in the tropics where flooding commonly occurs.
Potential Virulence Factors
The virulence factors of L. borgpetersenii have not been completely verified by current research. However, scientists have developed hypotheses that have been supported by the results of a few studies.
One possible virulence factor is the proteases that L. borgpetersenii is characterized with because they may facilitate tissue invasion, including 10 trypsin-like serine proteases, four zinc-dependent proteases, and a collagenase. An unusual vitamin K-dependent γ carboxylase, vgc, may affect hemostasis during infection . The inactivation of C3b may be the result of the attachment of factor H to the surface of L. borgpetersenii by LfhA, interfering with the complement cascade 
L. borgpetersenii has two unique N-acetylneuraminic acid synthetases that may prevent detection by the host immune system by coating the cell surface with sialic acid. L borgpetersenii disrupts cellular integrity through sphingomyelinases with its three sphingomyelinase genes .
L. borgpetersenii has a unique HA-like protein that may facilitate attachment to host tissue. Research suggests that L. borgpetersenii has the ligBgene to facilitate host cell attachment .
Clinical manifestations of Leptospirosis are misleading because they can be characterized with other diseases than mere Leptospirosis. Symptoms can range from a mild, flu-like illness to a severe disease form characterized by system complications in multiple organs, leading to death. Weil’s syndrome can ensue from contracting this bacteria as well. Severe disease is characterized by jaundice, acute renal and hepatic failure, pulmonary distress and hemorrhage, which can lead to death. Leptospirosis can also lead to kidney damage, meningitis, liver failure, and respiratory distress .
Leptospira can be cultured, but it can be a challenge diagnostically because the symptoms of this disease correlate with many tropical, febrile infections. . The MAb LD5 was used in a dot blot-enzyme-linked immunosorbent assay (dot-ELISA) for detecting Leptospira antigen in urine samples serially collected from two groups of patients diagnosed with leptospirosis in one study. Their serum samples were tested serologically by IgM Dipstick assay, indirect immunofluorescence assay (IFA), and/or microscopic agglutination test (MAT). The Leptospira antigenuria tested by the MAb-based dot-ELISA was positive for 75.0, 88.9, 97.2, 97.2, and 100% of patients on days 1, 2, 3, 7, and 14 of hospitalization, respectively . Also, antigen has been detected in the urine using the monoclonal antibody-based dot-ELISA .
Although most cases of leptospirosis have not been effectively treated by antibiotics, yet patients are still prescribed five to seven-day courses of antibiotic tablets. The preferred antibiotics for treatment include doxycycline, tetracycline, and doxycycline, and severe infection will require hospitalization .
Exposure to leptospirosis can be greatly reduced by limiting exposure to possibly contaminated water. One should not wade through water that has been in contact with urine of infected animals . Although there have been several vaccinations produced for animals due to its vast distribution, they are not 100% effective. The most highly effective vaccines for humans, however, were found to be a combination of inactivated and attenuated leptospirosis vaccines . Vaccines cannot guarantee safety, but research is being conducted and an ontology database has been established in hopes that a more effective vaccine can be formed.
Host Immune Response
Studies have shown that the humoral immune response largely mediates leptospirosis as the resistance mechanism . The antibodies produced during leptospiral infection were found to be IgM and IgG, and they were targeting the Gram-negative aspect of L. borgpetersenii by attacking the leptospiral LPS . LPS can activate the TLR4 pathway, but the presence of both TLR2 and TLR4 are vital if an innate immune response is expected to be effective. TLR4 was found to help the production of IgM by B cells to attack the LPS of L. borgpetersenii.
Because leptospire recognition in murine cells is mediated by both TLR4 and TLR2 receptors and only TLR2 is activated in human cells by LPS signals, it has been suggested that leptospiral lipid A is not recognized by human TLR4, and thus fails to activate this immune pathway . The lack of this recognition may be the reason there is leptospirosis susceptibility. Although the infection is not cleared by the innate immune response, macrophages have effectively phagocytosed leptospires in certain studies both in vivo and in vitro. However, the leptospires escaped from the phagosomes into the cytosol, and this is when proliferation and activated apoptosis occur.
Damage Response Framework
Currently, there is not enough research for microbiologists to develop a damage response framework. However, the incubation period has been estimated between 2--20 days. There is a broad range of symptoms, and none have been correlated with a particular causative agent or infectious dose amount.
1. Dieter M. Bulach, Richard L. Zuerner, Peter Wilson, Torsten Seemann, Annette McGrath, Paul A. Cullen, John Davis, Matthew Johnson, Elizabeth Kuczek, David P. Alt, Brooke Peterson-Burch, Ross L. Coppel, Julian I. Rood, John K. Davies, and Ben Adler Genome reduction in Leptospira borgpetersenii reflects limited transmission potentialPNAS 2006 103 (39) 14560-14565; published ahead of print September 14, 2006, <http://www.pnas.org/content/103/39/14560.long>
2. Evangelista KV, Coburn J. Leptospira as an emerging pathogen: a review of its biology, pathogenesis and host immune responses. Future microbiology. 2010;5(9):1413-1425. doi:10.2217/fmb.10.102. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037011/>
3. McBride A, Athanazio DA, Reis MG, Ko AI. Leptospirosis. Curr Opin Infect Dis. 2005;18(5):376–386.
4. . Natarajaseenivasan, Kalimuthusamy, Vedhagiri, Kumaresan, Sivabalan, Vadivel, Prabagaran, Shanmugarajan, Sukumar, Sethurajan, Artiushin, Sergey, Timoney, John. Division of Medical Microbiology, School of Life Sciences, Bharathidasan University, Tiruchirappalli, India. Seroprevalence of Leptospira borgpetersenii serovar javanica infection among dairy cattle, rats and humans in the Cauvery river valley of southern India. The Southeast Asian journal of tropical medicine and public health (Impact Factor: 0.55). 05/2011; 42(3):679-86. Source: PubMed <http://www.researchgate.net/publication/51251485_Seroprevalence_of_Leptospira_borgpetersenii_serovar_javanica_infection_among_dairy_cattle_rats_and_humans_in_the_Cauvery_river_valley_of_southern_India>
5. Knowles R., Das Gupta B.M. Leptospiral infection in Indian rats. Ind. J. Med. Res. 1932;54:611–614.
7. Rishavy MA , Hallgren KW , Yakubenko AV , Zuerner RL , Runge KW , Berkner KL (2005) J Biol Chem 280:34870–34877.
8. Verma A , Hellwage J , Artiushin S , Zipfel PF , Kraiczy P , Timoney JF , Stevenson B (2006) Infect Immun 74:2659–2666.
9. Matsunaga J , Barocchi MA , Croda J ,Young TA , Sanchez Y , Siqueira I , Bolin CA , Reis MG , Riley LW , Haake DA , et al.(2003) Mol Microbiol 49:929–945.
10. Calvo-Cano A, Aldasoro E, Ramírez MF, Martínez MJ, Requena-Méndez A, Gascón J. Two cases of laboratory-confirmed leptospirosis in travellers returning to Spain from Thailand, September 2013. Euro Surveill. 2014;19(2):pii=20675. <http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20675>
11. Saengjaruk P, Chaicumpa W, Watt G, et al. Diagnosis of Human Leptospirosis by Monoclonal Antibody-Based Antigen Detection in Urine. Journal of Clinical Microbiology. 2002;40(2):480-489. doi:10.1128/JCM.40.2.480-489.2002. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC153370/>
12. Wang Z, Jin L, Węgrzyn A. Leptospirosis vaccines. Microbial Cell Factories. 2007;6:39. doi:10.1186/1475-2859-6-39.
Created by KC Poe, a student of Dr. Tyrrell Conway, at the University of Oklahoma Italian Center