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Description
Leptospirosis, caused by the spirochete Leptospira interrogans and close relatives of
that genus, is a significant zoonotic disease affecting humans throughout the United Sates and
many other parts of the world. These bacteria infect humans and other animals by penetrating
mucous membranes or conjunctiva, or through breaks in the skin. Bacteria then disseminate
throughout the host via the bloodstream, followed by invasion of other tissues. Leptospirosis in
humans can lead to a range of debilitating symptoms, and, not infrequently, death.
Understanding the mechanisms by which leptospires are able to initiate and establish infection
can direct development of improved diagnostics and preventative/treatment therapies.
Infectious leptospires are very resistant to their hosts' alternative pathway of
complement-mediated killing. Our studies found that L. interrogans can bind the host
complement regulator factor H to its outer surface, a strategy adopted by many other pathogens
to avoid killing by host complement. During infection, L. interrogans invades and colonizes
kidneys and other host organs, apparently facilitated by the spirochete's abilities to interact with
host extracellular matrix (ECM) components. We discovered that L. interrogans carries six
separate but similar genes, each of which encodes a protein that can bind factor Hand/or ECM
proteins. All six leptospiral proteins share predicted structural and some functional similarities
with mammalian endostatin, and have been designated LenA, LenB, LenC, LenD, LenE and
LenF (Len = .Leptospiral _E_Ndostatin-like protein). We hypothesize that Len proteins enable L.
interrogans to both resist killing by host complement and to interact with host ECM. As a
corollary to our central hypothesis, we predict that all infectious leptospires produce one or more
Len proteins to facilitate mammalian infection, and that infected humans and other animals
produce antibodies against those Len proteins. To test our hypothesis, we will (1) perform
functional characterization of interactions between Len proteins and their host ligands and (2)
evaluate the practicality of using Len proteins for serological diagnosis of leptospirosis patients.
Status | Finished |
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Effective start/end date | 7/1/08 → 5/31/11 |
Funding
- National Institute of Allergy and Infectious Diseases: $402,875.00
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