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 #
5R01AI034431-16
Application #
8501228
Study Section
Special Emphasis Panel (ZRG1-IDM-A (02))
Program Officer
Mukhopadhyay, Suman
Project Start
1996-05-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
16
Fiscal Year
2013
Total Cost
$365,489
Indirect Cost
$41,338
Name
Brentwood Biomedical Research Institute
Department
Type
DUNS #
197170756
City
Los Angeles
State
CA
Country
United States
Zip Code
90073
Wunder Jr, Elsio A; Figueira, Claudio P; Santos, Gisele R et al. (2016) Real-Time PCR Reveals Rapid Dissemination of Leptospira interrogans after Intraperitoneal and Conjunctival Inoculation of Hamsters. Infect Immun 84:2105-15
Lourdault, Kristel; Matsunaga, James; Haake, David A (2016) High-Throughput Parallel Sequencing to Measure Fitness of Leptospira interrogans Transposon Insertion Mutants during Acute Infection. PLoS Negl Trop Dis 10:e0005117
Haake, David A; Levett, Paul N (2015) Leptospirosis in humans. Curr Top Microbiol Immunol 387:65-97
Haake, David A; Zückert, Wolfram R (2015) The leptospiral outer membrane. Curr Top Microbiol Immunol 387:187-221
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
Richer, Luciana; Potula, Hari-Hara; Melo, Rita et al. (2015) Mouse model for sublethal Leptospira interrogans infection. Infect Immun 83:4693-700
Coutinho, Mariana L; Matsunaga, James; Wang, Long-Chieh et al. (2014) Kinetics of Leptospira interrogans infection in hamsters after intradermal and subcutaneous challenge. PLoS Negl Trop Dis 8:e3307
Lourdault, Kristel; Wang, Long-Chieh; Vieira, Ana et al. (2014) Oral immunization with Escherichia coli expressing a lipidated form of LigA protects hamsters against challenge with Leptospira interrogans serovar Copenhageni. Infect Immun 82:893-902
Witchell, Timothy D; Eshghi, Azad; Nally, Jarlath E et al. (2014) Post-translational modification of LipL32 during Leptospira interrogans infection. PLoS Negl Trop Dis 8:e3280
Evangelista, Karen V; Hahn, Beth; Wunder Jr, Elsio A et al. (2014) Identification of cell-binding adhesins of Leptospira interrogans. PLoS Negl Trop Dis 8:e3215

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