The studies in this proposal will concentrate on the protein Tp92 from Treponema pallidum. This molecule was discovered during our initial granting period, and due to the predicted central role this molecule appears to play in T. pallidum pathogenesis it will be our primary research focus for this grant submission. Factors favoring the study of Tp92 include the observations that: 1) Tp92 homologs are widely distributed throughout gram-negative bacterial species; 2) Tp92 homologs are surface-exposed in Haemophilus influenzae and Pasteurella multocida, and elicit protection in an animal model of infection for each of these pathogens; 3) Tp92 knockout mutants have been non-viable in several bacterial species, suggesting this molecule is required for bacterial survival; 4) the T. pallidum Tp92 is a target of opsonic antibody; 5) immunization with Tp92 is partially protective for challenge against T. pallidum; 6) Tp92 does not appear to undergo antigenic variation in T. pallidum; and 7) preliminary evidence suggests the T. pallidum Tp92 facilitates cell binding through host cell integrin molecules. The long-term objective of these studies is to further our current knowledge of T. pallidum pathogenesis by providing an in depth and detailed study of one of the key molecules involved in pathogenesis of this bacterium. ? ? The following four specific aims are proposed:
Aim 1. Investigate the cell-binding function of the Tp92 molecule.
Aim 2. Determine the potential of the putative chaperone Tp0327 to interact with Tp92 and other T. pallidum outer membrane proteins.
Aim 3. Express Tp92 in a heterologous system to determine localization, interaction with Tp0327, and for epitope mapping.
Aim 4. Map key determinants of Tp92 for protection and for the immune response. ? ? It is expected that these studies will provide insights into the function of the Tp92 protein in binding cells via integrins, which is likely to be a pathogenic mechanism of T. pallidum. It is also expected that these studies will define the interaction of Tp92 with a putative chaperone and this interaction is likely to be necessary for proper insertion of Tp92 in the outer membrane. Finally, these studies will help define the protective immune response that results after immunization with Tp92 as well as the immune response to Tp92 that occurs during infection. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043456-09
Application #
7383168
Study Section
Special Emphasis Panel (ZRG1-BM-1 (01))
Program Officer
Hiltke, Thomas J
Project Start
1999-09-28
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2010-03-31
Support Year
9
Fiscal Year
2008
Total Cost
$317,281
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Van Voorhis, Wesley C; Barrett, Lynn K; Lukehart, Sheila A et al. (2003) Serodiagnosis of syphilis: antibodies to recombinant Tp0453, Tp92, and Gpd proteins are sensitive and specific indicators of infection by Treponema pallidum. J Clin Microbiol 41:3668-74
Morgan, Cecilia A; Lukehart, Sheila A; Van Voorhis, Wesley C (2003) Protection against syphilis correlates with specificity of antibodies to the variable regions of Treponema pallidum repeat protein K. Infect Immun 71:5605-12
LaFond, Rebecca E; Centurion-Lara, Arturo; Godornes, Charmie et al. (2003) Sequence diversity of Treponema pallidum subsp. pallidum tprK in human syphilis lesions and rabbit-propagated isolates. J Bacteriol 185:6262-8

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