Monday article #9: Leptospirosis – a neglected zoonotic disease

Introduction

Leptospirosis is a zoonosis bacterial infection that is emerging as a public health concern with significant impact around the world. Leptospirosis is often difficult to diagnose both in the clinical and laboratory. Therefore, the disease is frequently underreported in many countries and consequently severely neglected. It is usually transmitted through skin or mucus membrane contact with water or soil contaminated with urine from infected animals. Leptospirosis are widespread mostly in tropical countries with humid climates and has epidemic potential.



Microbiology

Leptospirosis is caused by the pathogenic genus Leptospira. This species is in a spirochetes form that has a tightly coiled lipopolysaccharides (LPS) outer membrane which enables them to survive in diverse environments. Leptospires are obligate aerobes with filaments that enable motility in liquid media such as blood, urine, and cerebrospinal fluid where they commonly reside. This species requires dark-field or phase contrast microscopy for visualization because leptospires Gram stains poorly. Pathogenic bacteria are generally from the leptospira interrogans genomospecies and there are eleven detected species of leptospira while thirty-seven serovars were found from wildlife and humans. According to the World Health Organization (WHO), it has been predicted that there are more than 240 pathogenic serovars which still cannot be differentiated based on morphology.

Scanning electron micrograph of L. interrogans serovar icterohaemorrhagiae strain RGA bound to a 0.2-μm membrane filter (Levett, 2001).



Transmission and risk of infection

The infection route is through abrasions or cuts in the skin, or through the conjunctiva and mucous membranes. This may occur through direct contact with an infected animal or through indirect contact via soil or water contaminated with urine from an infected animal. Besides that, individuals with occupations at risk for direct contact with potentially infected animals include veterinarians, animal shelter workers, scientists and technologists handling animals in laboratories or during fieldwork. The magnitude of risk depends on the degree and frequency of exposure. However, this exposure is not much of a risk as the individuals are covered by occupational health and safety regulations.


Indirect contact with water or soil contaminated with leptospires is more common and can be associated with occupational and recreational activities. Examples of outdoor work that are risk associated includes, sewer work, military exercises, and farming in high rainfall tropical regions. Based on the listed outdoor work, agricultural work involves activities likely to result in exposure of cuts and abrasions to soil and water contaminated with the urine of rodents. For example, banana workers accounted for two-thirds of the reported leptospirosis cases in a tropical region of Queensland, Australia.


Recreational exposures include all freshwater sports example, canoeing, kayaking, rafting and caving. Over the past 20 years, the importance of this type of exposure has increased as the popularity of adventure sports and race has increased. These competitive events create the potential for large outbreaks. According to the Eco-challenge and Springfield triathlon competition that took place during 2000, 80 and 98 leptospirosis cases occurred. This outbreak complicated the investigation as all the participants in international become ill after having returned home to multiple destination countries.


Avocational exposures are the most devastating compared to others. It affects millions of people living in tropical regions due to lack of adequate sanitation and poor housing combine which increases the risk of exposure to leptospires. These factors most likely attract rats, especially towards uncollected trash which also increases the risk of leptospirosis among residents of urban slums. More recently, climate change has been identified as a significant risk which includes, flashfloods and hurricanes.



Pathology of the transmission

First step: -

  • Leptospirosis penetrates of the tissue barriers to gain entrance to the body.

  • Potential portals of entry include the skin via a cut or abrasion and the mucous membranes of the conjunctivae or oral cavity.

Second step: -

  • Hematogenous dissemination.

  • Leptospires make their way into the bloodstream and persist there during the leptospiremic phase of the illness.

Third step: -

  • Diagram below shows the summary of immune responses induced by Leptospira sp. Infection (Gomes-Solecki, 2017).


Innate immune response

  • Toll-like receptor 2 (TLR2) can recognize the polysaccharide or 2-keto-3-deoxyoctonoic acid (KDO) component of leptospiral LPS.

  • TLR2, TLR4 and other innate immune response mechanisms are responsible for the host response to leptospiral infection that leads to symptoms of disease.

Systemic immune response

  • When high levels of leptospiremia occur during infection, innate immune mechanisms eventually trigger tissue-based and systemic responses to infection that lead to severe outcomes which includes organ failure.

  • Patients with severe leptospirosis have evidence of a “cytokine storm” with higher levels of IL-6, TNF-alpha, and several other cytokines.

  • The liver is a major target organ and causes pathological changes in lung.


Are Leptospirosis considered a multi-drug resistant pathogen?

Even though it’s not considered as a globally widespread disease, Leptospira spp. are intrinsically resistant to several antimicrobial classes; however, there is little evidence in the literature for development of acquired resistance to antimicrobial agents used for clinical treatment of acute leptospirosis.


  • Based on a study, the tested leptospirosis studies were found to be resistance towards amphotericin B, 5-fluorouracil, fosfomycin, trimethoprim, sulfamethoxazole, neomycin, and vancomycin.

  • However, for now Leptospirosis infections were found to be sensitive to ampicillin, cefotaxime, ciprofloxacin, norfloxacin, doxycycline, erythromycin, and streptomycin.

  • The apparent lack of any significant emergence of antimicrobial agent resistance in Leptospira raises an interesting question. Why has this not occurred?

  • Leptospiral infections are usually monomicrobial, with leptospires present in internal organs, such as blood, liver, spleen, lungs, and renal proximal tubules. The opportunity for horizontal resistance gene acquisition from other bacterial species is therefore minimal.

  • In addition, there is no experimental evidence to date of uptake of foreign DNA by Leptospira spp., although genomic analyses support this notion. Finally, in human’s leptospirosis is a dead-end infection; human-to-human transmission is so rare as to be considered insignificant.




References
  • Dechet, A. M., Parsons, M., Rambaran, M., Mohamed-Rambaran, P., Florendo-Cumbermack, A., Persaud, S., Baboolal, S., Ari, M. D., Shadomy, S. V., Zaki, S. R., Paddock, C. D., Clark, T. A., Harris, L., Lyon, D., & Mintz, E. D. (2012). Leptospirosis outbreak following severe flooding: a rapid assessment and mass prophylaxis campaign; Guyana, January-February 2005. PloS one, 7(7), e39672. https://doi.org/10.1371/journal.pone.0039672

  • Gomes-Solecki, M., Santecchia, I., & Werts, C. (2017). Animal models of leptospirosis: of mice and hamsters. Frontiers in immunology, 8, 58.

  • Haake, D. A., & Levett, P. N. (2015). Leptospirosis in humans. Current topics in microbiology and immunology, 387, 65–97. https://doi.org/10.1007/978-3-662-45059-8_5

  • Ko, A. I., Goarant, C., & Picardeau, M. (2009). Leptospira: the dawn of the molecular genetics era for an emerging zoonotic pathogen. Nature Reviews Microbiology, 7(10), 736-747.

  • Levett P. N. (2001). Leptospirosis. Clinical microbiology reviews, 14(2), 296–326. https://doi.org/10.1128/CMR.14.2.296-326.2001

  • Picardeau, M. (2017). Virulence of the zoonotic agent of leptospirosis: still terra incognita?. Nature Reviews Microbiology, 15(5), 297-307.


This article was prepared by,

Tanessri Muni Peragas

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