Antigenic variation of TprK

TprK 的抗原变异

• 批准号: 6892271
• 负责人: Sheila A. Lukehart
• 金额: $ 30.32万
• 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/6892271
• 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梅毒致病菌梅毒螺旋体的旁系同源 12 成员 tpr 家族。证据表明；这些：基因；及其编码的蛋白质，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，将其视为：梅毒螺旋体中第一个被描述的抗原变异系统。 TprK 是细胞和体液免疫的主要靶标，用重组 TprK 免疫兔子可显着减弱活梅毒螺旋体皮内攻击后病变的发展。 TprK 在菌株*之间和内部具有异质性，序列变异仅限于作为抗体反应目标的 7 个离散变量 (V)。已经提出了序列变异的分子机制，通过位于染色体上 tprD 附近的供体位点的基因转换，在单个 tprK 表达位点中产生突变。使用一种衍生梅毒螺旋体克隆分离株的新方法，我们证明了 tprK V 区序列在感染过程中发生变化，并且变异在免疫压力下累积。这些发现强烈表明 tprK 变异在免疫逃避和感染持续性中的作用。在此续展申请中，我们提出以下具体目标： 1)。比较三种梅毒株在感染过程和连续传代过程中tprK序列变化的模式和比率； 2）。确定免疫抑制是否可以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 区序列多样性对异源感染或免疫逃逸易感性的贡献。这些研究与项目 1-3 的目标相一致，将有助于确定这种重要感染的发病机制和持续性。