Surface Antigens of Treponema pallidum

描述（由申请人提供）：本提案的研究将集中在梅毒螺旋体蛋白Tp92上。该分子是在我们最初的授权期间发现的，由于该分子在T. pallidum发病机制中似乎起着预测的核心作用，它将成为我们本次拨款申请的主要研究重点。研究Tp92的有利因素包括：1)Tp92同源物广泛分布于革兰氏阴性菌；2) Tp92同源物在流感嗜血杆菌和多杀性巴氏杆菌中表面暴露，并在感染这些病原体的动物模型中引起保护；3) Tp92敲除突变体在一些细菌物种中无法存活，这表明这种分子是细菌生存所必需的；4)白螺旋体Tp92是opsonic抗体的靶点；5) Tp92免疫对白僵菌有部分保护作用；6) Tp92在苍白球绦虫中不存在抗原变异；7)初步证据表明，T. pallidum Tp92通过宿主细胞整合素分子促进细胞结合。这些研究的长期目标是通过对参与该细菌发病机制的关键分子之一进行深入和详细的研究，进一步加深我们目前对梅毒螺旋体发病机制的了解。

DESCRIPTION (provided by applicant): 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.