Surface Antigens of Treponema pallidum

描述(申请人提供)：本提案中的研究将集中在梅毒螺旋体的Tp92蛋白上。该分子是在我们最初的赠款期间被发现的，由于预测该分子似乎在梅毒螺旋体致病中发挥核心作用，它将是我们这次赠款提交的主要研究重点。支持Tp92研究的因素包括：1)Tp92同源物广泛分布于革兰氏阴性细菌物种中；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，并在动物感染模型中对这些病原体产生保护；3)Tp92基因敲除突变体在几个细菌物种中不存在，表明该分子是细菌生存所必需的；4)梅毒螺旋体Tp92是调理抗体的靶标；5)Tp92免疫对梅毒螺旋体的攻击具有部分保护作用；6)Tp92在梅毒螺旋体中似乎没有发生抗原性变异；7)初步证据表明，梅毒螺旋体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深入和详细地研究参与梅毒螺旋体致病的关键分子之一来加深我们目前对梅毒螺旋体致病机理的认识。 目的1.研究Tp92分子的细胞结合功能。目的2.确定可能的伴侣蛋白Tp0327与Tp92和其他梅毒螺旋体外膜蛋白的相互作用。目的3.在异源系统中表达Tp92，以确定Tp92的定位、与Tp0327的相互作用，并用于表位定位。目的4.绘制Tp92的关键决定因素图，用于保护和免疫反应。 预计这些研究将对Tp92蛋白通过整合素结合细胞的功能提供见解，这可能是梅毒螺旋体的致病机制。预计这些研究将确定Tp92与假定的伴侣之间的相互作用，这种相互作用可能是Tp92正确插入外膜所必需的。最后，这些研究将有助于确定Tp92免疫后产生的保护性免疫反应以及感染期间发生的对Tp92的免疫反应。

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.