Leptospirosis is a neglected emerging zoonotic disease with worldwide distribution that affects virtually all vertebrates. It is a burden on society due to elevated morbidity in humans (~1 million cases a year, 5 to 10% mortality rate) and extensive loss of animals of agricultural interest. Traditionally, leptospirosis is more common in tropical regions. However, an outbreak was reported in New York City recently. There is no vaccine approved for human use in the US and antibiotic treatment is only effective if used early in the course of infection. Critical barriers in the development of effective countermeasures against leptospirosis are: 1) absence of an inbred immunocompetent mouse model amenable to in-depth characterization of host factors underlying virulence, disease pathology and vaccine efficacy mechanisms; and 2) lack of non-toxic recombinant based shedding-blocking vaccines. The ultimate goal of this project is to develop immunocompetent mouse models of persistent leptospirosis, suitable for consistent measurement of Leptospira shedding in urine. Another goal is to test new, bi-functional recombinant based vaccine candidates, as well as established bacterins, to evaluate efficacy of new vaccine candidates and validate the mouse model. Our central hypothesis is that we can use TLR4 humanized transgenic mice as immunocompetent models of leptospirosis. The short-term impact of this 2-year proposal relates to development of mouse models that mimic sublethal and chronic leptospirosis that can be used to test shedding-blocking vaccines as well as adjuvants that signal through TLR4. The long-term impact of this proposal is conceptual and relates to the study of persistence of a spirochetal pathogen in an immunocompetent mouse model.

Public Health Relevance

Leptospirosis is a burden on society due to elevated morbidity in humans (~1 million cases a year, 5 to 10% mortality rate) and extensive loss of animals of agricultural interest, worldwide. Although leptospirosis is more common in tropical regions, an outbreak was reported in New York City in February of 2017, and there is no vaccine approved for human use in the US. The goals of this project are 1) to develop humanized immunocompetent mouse models of persistent leptospirosis; and 2) to validate the model using new and established vaccine candidates for leptospirosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI142129-01A1
Application #
9823538
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mukhopadhyay, Suman
Project Start
2019-06-01
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38103