EXPRESSION AND FUNCTION OF MSP HOMOLOGUES IN T PALLIDUM

随着原发性梅毒的消退，大部分梅毒原体从下疳清除。然而，少数生物体逃脱免疫反应，引起继发性梅毒，并最终建立慢性感染。人们提出了许多理论来解释梅毒螺旋体的免疫逃避能力，但没有一个理论有令人信服的实验支持。抗原变异是最有趣的理论之一，但直到现在还没有确定候选抗原。最近在T. pallidum中发现了一个多态性多拷贝基因家族，该基因家族编码与密螺旋体主要鞘蛋白（msp）同源的氨基酸，提供了一个可能的候选家族。我们称这些苍白t蛋白为msp同源物。该建议的主要目标是确定msp同源蛋白的细胞位置和功能。该项目的具体目标如下：1。确定白球绦虫尼科尔斯菌株的msp同源物是否为表面暴露抗原。这一目的将检验一些msp同源物在生物体中表面暴露的假设。2. 确定msp同源物是否参与细胞附着和作为孔蛋白的功能。这一目的将确定msp同源家族是否在两种公认的细菌感染发病机制中起作用。3. 确定白螺旋体尼科尔斯菌株是否代表一个菌落种群或由密螺旋体亚种群组成。这一目标将验证一种假设，即像其他螺旋体一样，苍白螺旋体菌株含有表达异质msp同源物的亚群。4. 确定msp同源物是否经历抗原变异或相变异。抗原性变异在其他致病性密螺旋体中很常见，msp同源基因家族具有高度提示基因重组和重配的特征。这一目的将检验在感染过程中单个msp同源物发生变化（抗原变异）或不再表达（期变异）的假设。在本应用中提出的研究将确定msp-同源物在免疫逃避和梅毒发病机制中的作用。

As primary syphilis resolves, most treponemes are cleared from the chancre. However, a few organisms escape the immune response to cause secondary syphilis and ultimately to establish chronic infection. May theories have been proposed to explain Treponema pallidum's capacity for immune evasion, yet none has convincing experimental support. Antigen variation is one of the most intriguing theories, but not candidate antigens have been identified until now. The recent identification of a polymorphic multicopy gene family in T. pallidum that encodes for proteins with predicated amino acid homology to the major sheath protein (msp) of Treponema denticola provides a family of likely candidates. We call these T. pallidum proteins the msp-homologues. The broad goal of this proposal is to determine the cellular location and the function of the msp-homologue proteins. The specific aims of the project are the following: 1. Determine whether msp-homologues are surface exposed antigens in T. pallidum Nichols strain. This aim will test the hypothesis that some of the msp-homologues are surface exposed in living organisms. 2. Determine whether msp-homologues are involved in cell attachment and function as porins. This aim will determine whether the msp-homologue family has a role in two well-recognized mechanisms of pathogenesis of bacterial infections. 3. Determine whether T. pallidum Nichols strain represents a colonal bacterial population or is comprised of subpopulations of treponemes. This aim will test the hypothesis that, like other spirochetes, T. pallidum strains contain subpopulations that express heterogeneous msp- homologues. 4. Determine whether the msp-homologues undergo antigen variation or phase variation. Antigenic variation is common other pathogenic treponemes and the msp-homologue gene family has characteristics highly suggestive of genetic recombination and reassortment. This aim will test the hypothesis that individual msp-homologues either change (antigenic variation) or are no longer expressed (phase variation) during the course of infection. The studies proposed in this application will define the role of the msp- homologues in immune evasion and in the pathogenesis of syphilis.