Project 4: Antigenic variation of TprK

项目4：TprK的抗原变异

• 批准号: 7076206
• 负责人: Sheila A. Lukehart
• 金额: $ 29.61万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076206
• 关键词: Treponema pallidum; bacterial disease; bacterial genetics; bacterial proteins; gene conversion; gene mutation; humoral immunity; immune response; immunosuppression; laboratory rabbit; polymerase chain reaction; suppressor T lymphocyte; syphilis

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.

该计划项目申请的重点是Causatiye treponema Pallidum的12个核心TPR家族；有证据表明；这些：基因；它们的编码蛋白是重要的抗原和毒力因子。我们建议检查TPR家族的一个成员TPRK，AS：第一个在treponema pallidum中依次的天形变异系统。 TPRK是细胞和体液免疫和免疫兔的主要靶标，具有重组TPRK，导致在皮内挑战和可行的毛毛虫pallidum pallidum的皮内攻击后显着衰减病变的发育。 TPRK在菌株*之间是异质的，序列变化限制为7个离散变量（V），这是抗体响应的靶标。已经提出了用于序列变异的分子机制，通过基因转化在染色体上TPRD附近的供体位点的基因转化在单个TPRK表达位点出现突变。使用一种新的方法来衍生胶原杆菌的克隆分离株，我们证明了TPRK V区域序列在感染过程中发生变化，并且在免疫压力下的变异积累。这些发现强烈表明TPRK变异在免疫逃避和感染的持久性中的作用。在此续签应用中，我们提出以下特定目的：1）。比较在感染过程和串行过程中，TPRK序列变化的模式和速率变化； 2）。确定免疫抑制是否防止感染过程中变异序列的积累； 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区域序列多样性对异源感染或免疫逃生的敏感性的贡献。这些研究符合项目1-3的目的，将有助于确定这种重要感染的发病机理和持久性机制。