Antigenic variation of TprK

该程序项目申请的重点是梅毒螺旋体（Treponema pallidum）的12个成员的tpr家族，病原体；梅毒的病原体。证据显示;这些：基因；它们编码的蛋白质是重要的抗原和毒力因子。我们建议检查TprK， Tpr家族的一个成员，作为梅毒螺旋体中描述的第一个基因变异系统。TprK是细胞免疫和体液免疫的主要靶点，重组TprK免疫兔可显著减弱活螺旋体皮内攻击后病变的发展。TprK在株间和株内*具有异质性，序列变异仅限于抗体应答目标的7个离散变量(V)。已经提出了序列变异的分子机制，通过染色体上靠近tprD的供体位点的基因转换，在单个tprK表达位点发生突变。我们利用一种新的方法推导了白僵菌克隆分离株，证明了tprK V区序列在感染过程中发生变化，并且这种变化在免疫压力下积累。这些发现强烈提示tprK变异在免疫逃避和感染持续中的作用。在本次续约申请中，我们提出以下具体目标：1)。比较三株苍白球绦虫在感染过程和连续传代过程中tprK序列的变化模式和速率；2）. 确定免疫抑制是否能防止感染期间变异序列的积累；3）. 确定V区特异性免疫压力是否选择具有变异tprK序列的生物体；4)。确定TprK V区序列多样性对异种感染或免疫逃逸易感性的贡献。这些研究与项目1-3的目标一致，将有助于确定这种重要感染的发病机制和持久性。

This Program Project application focuses on the paralogous 12-mernber tpr family of Treponema pallidum, the causatiye;agent of syphilis. Evidence suggests; that these: genes; and their encoded proteins, are important antigens and virulence factors. We propose to examine TprK, one member of the Tpr family, as:the first angenic variation system to bedescribed in Treponema pallidum. TprK is a major target of both cellular and humoral immunity and immunization rabbits with recombinant TprK results in significant attenuation of lesion development following intradermal challenge with viable Treponema pallidum. TprK is heterogeneous among and within strains* with sequence variation limited to 7 discrete variable (V) that are targets of the antibody response. A molecular mechanism has been proposed for the sequence variation, with mutations arising in the single tprK expression site by gene conversion of donor sites located near tprD on the chromosome. Using a novel method for derivation of clonal isolates of T. pallidum, we have demonstrated that the tprK V region sequences change during infection, and that variation accumulates under immune pressure. These findings strongly suggest the role of tprK variation in immune evasion and persistence of infection. In this renewal application, we propose the following Specific Aims: 1). Compare the pattern and rate of tprK sequence change among three strains of T. pallidum during the course of infection and during serial passage; 2). Determine whether immunosuppression prevents accumulation of variant sequences during infection; 3). Determine whether V region-specific immune pressure selects for organisms with variant tprK sequences; 4). Determine the contribution of TprK V region sequence diversity in susceptibility to heterologous infection or immune escape. These studies, in concert with the aims of Projects 1-3, will help to define mechanisms of pathogenesis and persistence of this important infection.