EXPRESSION AND FUNCTION OF MSP HOMOLOGUES IN T PALLIDUM

随着一期梅毒消退，大部分梅毒螺旋体从下疳中清除。然而，少数微生物逃避免疫反应，引起二期梅毒，并最终建立慢性感染。已经提出了可能的理论来解释梅毒螺旋体的免疫逃避能力，但没有一个有令人信服的实验支持。抗原变异是最有趣的理论之一，但迄今为止尚未发现候选抗原。最近发现的一个多态性多拷贝基因家族。编码与齿垢密螺旋体的主要鞘蛋白（MSP）具有预测氨基酸同源性的蛋白质的苍白球蛋白提供了一个可能的候选物家族。我们称之为T。苍白球蛋白是MSP同源物。这个提议的主要目标是确定msp同源蛋白的细胞定位和功能。该项目的具体目标如下：1.确定msp同源物是否是T. pallidum Nichols菌株这一目标将测试的假设，一些msp同源物的表面暴露在活的生物体。2.确定msp同源物是否参与细胞附着并作为孔蛋白发挥功能。这一目标将确定msp同源家族是否在两种公认的细菌感染发病机制中发挥作用。3.确定T.苍白球Nichols菌株代表一个结肠细菌群体或由密螺旋体亚群组成。这一目标将检验这一假设，即像其他螺旋体一样，T。苍白球菌株含有表达异质MSP同源物的亚群。4.确定msp同源物是否经历抗原变异或相位变异。抗原变异是常见的其他致病性密螺旋体和msp同源基因家族的特点，高度提示遗传重组和重配。这一目标将测试的假设，个别的MSP同源物改变（抗原变异）或不再表达（时相变化）在感染过程中。本申请中提出的研究将确定MSP-同系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.