Surface Antigens of Treponema pallidum

描述（由申请方提供）：本提案中的研究将集中于梅毒螺旋体的蛋白TP 92。这种分子是在我们最初的授权期间发现的，由于预测的核心作用，这种分子似乎在T。苍白球的发病机制，这将是我们的主要研究重点，为这项拨款提交。有利于研究Tp 92的因素包括以下观察结果：1）Tp 92同源物广泛分布于革兰氏阴性细菌物种中; 2）Tp 92同源物在流感嗜血杆菌（Haemophilus influenzae）和多杀性巴氏杆菌（Pasteurella multocida）中表面暴露，并且在感染这些病原体中的每一种的动物模型中引起保护; 3）Tp 92敲除突变体在几种细菌中不能存活，表明该分子是细菌存活所必需的; 5）Tp 92免疫对T. 6）Tp 92在T. pallidum; 7）初步证据表明T.苍白球Tp 92通过宿主细胞整联蛋白分子促进细胞结合。这些研究的长期目标是进一步加深我们目前对T。苍白球的发病机制，提供了一个深入和详细的研究，在这种细菌的发病机制的关键分子之一。 提出了以下四个具体目标：目标1。研究Tp 92分子的细胞结合功能。目标二。确定推定的伴侣蛋白Tp 0327与Tp 92和其他T.苍白球外膜蛋白目标3。在异源系统中表达Tp 92以确定定位、与Tp 0327的相互作用以及用于表位作图。目标4。绘制TP 92保护和免疫应答的关键决定因素。 这些研究将有助于深入了解Tp 92蛋白通过整合素结合细胞的功能，这可能是T.苍白球还预期这些研究将确定Tp 92与推定的伴侣蛋白的相互作用，并且这种相互作用对于Tp 92在外膜中的适当插入可能是必要的。最后，这些研究将有助于确定TP 92免疫后产生的保护性免疫应答以及感染期间发生的对TP 92的免疫应答。

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.