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. ? ?
Showing the most recent 10 out of 13 publications
