Animal Models of Leptospirosis: Of Mice and Hamsters

Abstract

Pathogenic Leptospira sp. are spirochetal bacteria responsible for leptospirosis, an emerging worldwide zoonosis. These spirochetes are very successful pathogens that infect a wide range of hosts such as fish, reptiles, birds, marsupials, and mammals. Transmission occurs when chronically infected animals excrete live bacteria in their urine, contaminating the environment. Leptospira sp. enter their hosts through damaged skin and mucosa. Chronically infected rats and mice are asymptomatic and are considered as important reservoirs of the disease. Infected humans may develop either a flu-like, usually mild illness with or without chronic asymptotic renal colonization, or a severe acute disease with kidney, liver, and heart failure, potentially leading to death. Leptospirosis is an economic burden on society due to health-care costs related to elevated morbidity of humans and loss of animals of agricultural interest. There are no effective vaccines against leptospirosis. Leptospira sp. are difficult to genetically manipulate which delays the pace of research progress. In this review, we discuss in an historical perspective how animal models have contributed to further our knowledge of leptospirosis. Hamsters, guinea pigs, and gerbils have been instrumental to study the pathophysiology of acute lethal leptospirosis and the Leptospira sp. genes involved in virulence. Chronic renal colonization has been mostly studied using experimentally infected rats. A special emphasis will be placed on mouse models, long thought to be irrelevant since they survive lethal infection. However, mice have recently been shown to be good models of sublethal infection leading to chronic colonization. Furthermore, congenic and transgenic mice have proven essential to study how innate immune cells interact with the pathogen and to understand the role of the toll-like receptor 4, which is important to control Leptospira sp. load and disease. The use of inbred and transgenic mouse models opens up the field to the comprehensive study of immune responses to Leptospira sp. infection and subsequent pathophysiology of inflammation. It also allows for testing of drugs and vaccines in a biological system that can avail of a wealth of molecular tools that enable understanding of the mechanisms of action of protective vaccines.

A Live Attenuated Vaccine Model Confers Cross-Protective Immunity Against Different Species ofLeptospiraspp.

“…In our hamster model we observed a significant reduction of the bacterial burden in the kidney of vaccinated animals, without significant levels of protection. Mice models are good alternatives for sublethal leptospirosis infection and particularly to study renal colonization, compared to the highly susceptible hamster model 30 . Previous experiments in mice showed that if the challenge dose is not able to cause death of the animals, a portion of the sublethal dose of leptospires is able to escape the blood defenses and colonize the kidneys 31 .…”

“…Hamsters vaccinated with the heat-killed vaccine were only challenged with Fiocruz L1-130 (homologous) or Manilae L495 (heterologous) strains. Mice were challenged intraperitoneally with L. interrogans serovar Manilae L495 (10 8 leptospires) 30,31 . After euthanizing the animals, kidneys were collected and stored as described above.…”

Leptospirosis in an asplenic patient -case report

“…We attempted Leptospira isolation during the leptospiremic phase in the hamster model, based on previous studies [9]. Nonetheless, Leptospira isolation and culture are difficult to be obtained; its persistence depends on the serovar [9,48]. In particular, serovar Bratislava and close related strains are fastidious serovars [34].…”

Comparative screening of recombinant antigen thermostability for improved leptospirosis vaccine design

“…Vaccine trials with the C‐terminal domains of LigA have shown protection that is more consistent than with other Lig protein segments (Adler, ). While these results suggest a possible link between domain stability and protection consistency, leptospirosis challenge experiments have many notable issues, including the animal model (Gomes‐Solecki, Santecchia, & Werts, ), the challenge strain (Fouts et al, ), the delivery method (Coutinho et al, ), and the use of adjuvants, that can each cause variability between vaccine trials (Vernel‐Pauillac & Werts, ). Comparing two recent LigB studies that used different adjuvants, the trial that incorporated the potent Alum adjuvant provided sterilizing immunity (Conrad et al, ), whereas the other trial used mycobacterial‐derived Freund adjuvant and did not provide complete protection (Evangelista et al, ).…”