Pathogenesis of Leptospira

Leptospirosis is a neglected life-threatening disease occurring in a diverse range of epidemiological settings. However, the large majority of the burden occurs in the world’s most impoverished populations. The causative agents are a genetically and antigenically diverse group of spirochetes divided into eleven pathogenic Leptospira species and >200 serovars. Leptospires are able to establish acute disease in susceptible hosts, chronic carriage in the proximal kidney tubules of a broad range of mammalian reservoir hosts, and persist for weeks to months in the environment after excretion. Leptospires are highly motile spirochetes that penetrate abraded skin and mucous membranes and cross tissue barriers to disseminate hematogenously resulting in a systemic infection. Leptospirosis is an environmentally-transmitted disease since the primary mode of transmission to humans is contact with contaminated water or soil. The disease causes life-threatening manifestations such as pulmonary hemorrhage syndrome (LPHS) and Weil’s disease and has emerged as a major worldwide cause of hemorrhagic fever and acute kidney injury. These estimates place leptospirosis as a leading zoonotic cause of morbidity and mortality worldwide. Mortality from severe leptospirosis is high (>10%) despite aggressive supportive care. Timely diagnosis requires a laboratory test since the clinical presentation of early phase leptospirosis is non-specific. However, current diagnosis relies on antiquated or low performance methods. The lack of adequate diagnostics has not only hampered outpatient-based interventions aimed at reducing the high mortality due to leptospirosis, but contributed to the under-recognition of its disease burden and neglected disease status. A major impediment to identifying new approaches to intervention has been the limited understanding of the disease determinants. The development of leptospirosis and disease progression are influenced by the susceptibility of the host, the virulence of the infecting strain, and the initial inoculum dose of infection. Despite the sizeable burden of disease associated with leptospirosis, the biological mechanisms of pathogenesis associated with Leptospira remain poorly understood.