Slideshow Image

Leptospiral Research

Leptospirosis is a neglected global human health problem caused by transmission from reservoir hosts that harbor pathogenic Leptospira species in their kidneys and shed them into the environment in their urine.  Our long-term goal is to understand the role(s) of surface-exposed outer membrane proteins (OMPs) in the mechanisms of leptospiral pathogenesis and immunity (1).

Surface-exposed OMPs.  We have developed a number of methods for identifying surface-exposed OMPs and secreted proteins that are expressed during mammalian host infection and are involved in key host-pathogen interactions (2).  Surface-exposed OMPs include both transmembrane OMPs and lipoproteins, including the leptospiral immunoglobulin-like (Lig) proteins, which exhibit high avidity binding to host ligands and inhibit fibrin formation (3,4).  In collaboration with Mathieu Picardeau and Albert Ko, we developed a surrogate host expression system for assessing the contribution of leptospiral OMPs to the adhesion phenotype of leptospiral cells (5).

OMP Gene Regulation.  Genome sequencing studies indicate that pathogenic Leptospira species have a rich diversity of signal transduction mechanisms (6).  Consistent with this, we have shown that osmolarity and temperature conditions found in host tissues rapidly and dramatically induce expression of LigA, LigB, and other leptospiral OMPs (7).  These data indicate that OMPs upregulated in vivo play key roles in leptospiral colonization of host tissues at portals of entry during acquisition and transmission of infection.   Surface-exposed OMPs that are upregulated during infection and mediate host tissue interactions are also important targets of a protective immune response.  We, and others, have shown that LigA is a potent protective immunogen (8) and we have now localized the key LigA protective epitopes to domains 10-13 (9).

1. Haake DA, Matsunaga J. Leptospira: a spirochaete with a hybrid outer membrane. Mol Microbiol. 2010;77:805-14.

2. Pinne M & Haake, DA.  A comprehensive approach to identification of surface-exposed outer membrane-spanning proteins of Leptospira interrogans.  PLoS ONE. 2009; 4:e6071.

3. Matsunaga J, Barocchi MA, Croda J, Young TA, Sanchez Y, Siqueira I, et al. Pathogenic Leptospira species express surface-exposed proteins belonging to the bacterial immunoglobulin superfamily. Mol Microbiol. 2003;49(4):929-45.

4. Choy HA, Kelley MM, Croda J, Matsunaga J, Babbitt JT, Ko AI, et al. The multifunctional LigB adhesin binds homeostatic proteins with potential roles in cutaneous infection by pathogenic Leptospira interrogans. PLoS ONE. 2011;6:e16879.

5. Figueira CP, Croda J, Choy HA, Haake DA, Reis MG, Ko AI, Picardeau M. Heterologous expression of pathogen-specific genes ligA and ligB in the saprophyte Leptospira biflexa confers enhanced adhesion to cultured cells and extracellular matrix components. BMC Microbiology. 2011;11:129.

6. Galperin MY. A census of membrane-bound and intracellular signal transduction proteins in bacteria: Bacterial IQ, extroverts and introverts. BMC Microbiol. 2005;5:35.

7. Matsunaga J, Lo M, Bulach DM, Zuerner RL, Adler B, Haake DA. Response of Leptospira interrogans to physiologic osmolarity: relevance in signaling the environment-to-host transition. Infect Immun. 2007;75(6):2864-74.

8. Silva EF, Medeiros MA, McBride AJ, Matsunaga J, Esteves GS, Ramos JB, et al. The terminal portion of leptospiral immunoglobulin-like protein LigA confers protective immunity against lethal infection in the hamster model of leptospirosis. Vaccine. 2007;25:6277-86.

9. Coutinho ML, Choy HA, Kelley MM, Matsunaga J, Babbitt JT, Lewis M, et al. A LigA three-domain region protects hamsters from lethal infection by Leptospira interrogans. PLoS Negl Trop Dis. 2011 December; 5(12); e1422.