EXPRESSION AND FUNCTION OF MSP HOMOLOGUES IN T PALLIDUM

随着一期梅毒的消退，大多数梅毒螺旋体从下巴中清除。然而，少数生物逃脱了免疫反应，导致二次梅毒，最终形成慢性感染。梅的理论已经被提出来解释梅毒螺旋体逃避免疫的能力，但没有一个有令人信服的实验支持。抗原变异是最耐人寻味的理论之一，但到目前为止还没有发现候选抗原。最近在梅毒螺旋体中发现了一个多态的多拷贝基因家族，该家族编码的蛋白质与齿密螺旋体的主鞘蛋白(MSP)具有预测的氨基酸同源性，提供了一个可能的候选家族。我们称这些梅毒螺旋体蛋白为MSP同源蛋白。这项建议的主要目标是确定MSP同源蛋白的细胞位置和功能。本研究的具体目的如下：1.确定梅毒螺旋体表面暴露抗原是否为梅毒螺旋体尼科尔斯株的表面暴露抗原。这一目标将检验这样一个假设，即一些MSP同系物在活体中暴露在表面。2.确定MSP-同系物是否参与细胞附着并作为孔蛋白发挥作用。这一目标将决定MSP同源家族是否在细菌感染的两种公认的发病机制中发挥作用。3.确定梅毒螺旋体Nichols株是否代表结肠菌群或由密螺旋体亚群组成。这一目标将检验这样一个假设，即像其他螺旋体一样，梅毒螺旋体菌株包含表达不同MSP同源物的亚群。4.确定MSP同系物是否发生抗原变异或时相变异。抗原变异是常见的其他致病性梅毒螺旋体，MSP同源基因家族具有高度提示遗传重组和重组的特征。这一目标将检验这样的假设，即在感染过程中，个别MSP同源物要么改变(抗原变异)，要么不再表达(阶段变异)。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.