Leptospirosis is the most widespread zoonotic disease worldwide, and is emerging as a significant infectious disease in urban slums, particularly in tropical regions. Several species of the genus Leptospira can cause infection, which can vary in severity from mild illness to fatal hemorrhagic disease with multiple organ failure. Typically, infection of a maintenance (reservoir) host is chronic and asymptomatic. Virtually all species of mammal can serve as reservoirs of the bacteria, with the survivors of infection harboring Leptospira in the proximal tubules of the kidney and excreting Leptospira in the urine. Release of viable bacteria into the environment provides opportunities for infection of new hosts. The persistence of leptospires in the kidneys of wildlife, companion animals, and livestock provides a constant reservoir for human infection. Despite the global burden of disease in humans and animals, the mechanisms used by Leptospira species to promote colonization, dissemination, and disease are not yet defined. While Leptospira species can disseminate to virtually any tissue, the epidemiologically critical site of persistent infection is the proximal tubules, in which spirochetes are clearly adherent to the luminal aspect of the epithelial cells. However, nothing is known about how pathogenic Leptospira species interact with host cells in the proximal tubules. Our hypothesis is that pathogenic Leptospira species attach to proximal tubule epithelial cells using specific adhesins targeting the host cell surface. We have demonstrated that L. interrogans binds to cells more efficiently than to the ECM deposited by the cells, and using phage display, identified several cell-specific adhesins based on selection for binding to endothelial cells. To fill a critical knowledge gap in understanding L. interrogans infection and pathogenesis, we will build on our expertise and reagents to select L. interrogans adhesins that mediate interactions with proximal tubule cells. We will then assess the candidate adhesins for binding to proximal tubule cells of additional species and to host cell receptors that that we have identified, for surface exposure on the bacteria, and for expression by the bacteria during leptospirosis infection. We anticipate that this work will expedite the identification of ne candidates for development of vaccines and therapeutic interventions that will disrupt the maintenance of pathogenic Leptospira species in animal reservoirs, thereby reducing risk of human and animal infections.

Public Health Relevance

Leptospirosis is a potentially fatal infectious disease, usually acquired from animals or water contaminated with their urine, with global distribution. The epidemiology of leptospirosis suggests that preventive measures, such as vaccines that are effective against diverse Leptospira strains, would have a significant impact on human and animal health. In the work proposed here we will identify leptospiral molecules required for the bacteria to bind to the type of cells important for persistent infection in animals, with the hope that this will eventually lead to improved vaccines.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI109649-01A1
Application #
8758246
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mukhopadhyay, Suman
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Milwaukee
State
WI
Country
United States
Zip Code
53226