Leptospirosis is considered by the Centers for Disease Control to be the most widespread zoonosis in the world. Reservoir hosts with chronic renal tubular infection typically transmit pathogenic Leptospira species to humans through urinary shedding. Leptospiral infection in humans frequently results in fulminate liver dysfunction, kidney failure, and severe pulmonary hemorrhage syndrome with a mortality rate of >10%. Leptospirosis has emerged as a major public health burden in urban slums where risk is strongly linked to poverty and rat exposure. L. interrogans serovar Copenhageni is the most common organism isolated from the urban brown rat (Rattus norvegicus) is also the predominant cause of human leptospirosis in urban slums. There is a need to develop oral vaccination strategies to prevent renal carriage in the reservoir host and the risk of leptospirosi in at-risk human populations. The overall goal of this proposal is to understand the role(s) of surface-exposed outer membrane proteins (OMPs) in the mechanisms of leptospiral pathogenesis and immunity. We hypothesize those OMPs that are unregulated as pathogenic leptospires transition from the environment into the mammalian host tissues are key targets for a protective immune response. In support of this hypothesis, we have found that the leptospiral immunoglobulin-like (Lig) proteins are dramatically unregulated by temperature and osmolarity, play multiple roles in host- pathogen interactions, and have been shown to be effective protective immunogens. We propose the following interrelated but not interdependent Aims: 1) Examine the transcriptional and post-transcriptional mechanisms that regulate Lig expression;2) Determine which surface-exposed OMPs are involved in mechanisms of leptospiral pathogenesis &immunity;3) Determine which leptospiral OMPs are most effective at inducing sterilizing immunity. In pursuit of these aims, we will examine the molecular mechanisms by which OMPs are regulated, identify additional OMP adhesions and examine their roles in pathogenesis and immunity, and develop E. coli and Lactobacillus oral OMP-based vaccines that prevent acquisition of renal infection by reservoir hosts and effectively block shedding of pathogenic leptospires. This information is critical to understanding how to reduce environmental contamination with and preventing exposure to these potentially life-threatening bacterial pathogens.

Public Health Relevance

Leptospirosis is an important global human health problem caused by transmission from rodents that harbor pathogenic Leptospira bacteria in their kidneys and shed them into the environment. We will develop outer membrane protein-based vaccines that prevent acquisition of renal infection by reservoir hosts and effectively block shedding of pathogenic leptospires.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI034431-17
Application #
8675783
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mukhopadhyay, Suman
Project Start
1996-05-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brentwood Biomedical Research Institute
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90073
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Gomes-Solecki, Maria; Santecchia, Ignacio; Werts, Catherine (2017) Animal Models of Leptospirosis: Of Mice and Hamsters. Front Immunol 8:58
Potula, Hari-Hara; Richer, Luciana; Werts, Catherine et al. (2017) Pre-treatment with Lactobacillus plantarum prevents severe pathogenesis in mice infected with Leptospira interrogans and may be associated with recruitment of myeloid cells. PLoS Negl Trop Dis 11:e0005870
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Richer, Luciana; Potula, Hari-Hara; Melo, Rita et al. (2015) Mouse model for sublethal Leptospira interrogans infection. Infect Immun 83:4693-700
Narayanavari, Suneel A; Lourdault, Kristel; Sritharan, Manjula et al. (2015) Role of sph2 Gene Regulation in Hemolytic and Sphingomyelinase Activities Produced by Leptospira interrogans. PLoS Negl Trop Dis 9:e0003952

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