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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mukhopadhyay, Suman
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brentwood Biomedical Research Institute
Los Angeles
United States
Zip Code
Gomes-Solecki, Maria; Richer, Luciana (2018) Recombinant E. coli Dualistic Role as an Antigen-adjuvant Delivery Vehicle for Oral Immunization. Methods Mol Biol 1690:347-357
Lourdault, Kristel; Matsunaga, James; Evangelista, Karen V et al. (2017) High-throughput Parallel Sequencing to Measure Fitness of Leptospira interrogans Transposon Insertion Mutants During Golden Syrian Hamster Infection. J Vis Exp :
Sullivan, Joseph Pierce; Nair, Nisha; Potula, Hari-Hara et al. (2017) Eyedrop Inoculation Causes Sublethal Leptospirosis in Mice. Infect Immun 85:
Ratet, Gwenn; Santecchia, Ignacio; Fanton d'Andon, Martine et al. (2017) LipL21 lipoprotein binding to peptidoglycan enables Leptospira interrogans to escape NOD1 and NOD2 recognition. PLoS Pathog 13:e1006725
Evangelista, Karen V; Lourdault, Kristel; Matsunaga, James et al. (2017) Immunoprotective properties of recombinant LigA and LigB in a hamster model of acute leptospirosis. PLoS One 12:e0180004
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
Haake, David A (2016) The Miller Hypothesis. For Immunopathol Dis Therap 7:167-174
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 84:2105-2115
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

Showing the most recent 10 out of 67 publications