Mechanisms of Gonococcal Pilin Antigenic/Phase Variation

描述（由申请人提供）：革兰氏阴性细菌淋病奈瑟菌是性传播疾病淋病的唯一病原体。淋球菌发病机制的一个重要方面是菌毛蛋白抗原变异（Av）的过程，其允许细菌的免疫逃避和通过感染人群的高风险/核心群体的持续重新传播。此外，菌毛功能的启动事件的殖民和菌毛的功能特性可以改变菌毛抗原变异。了解用于影响和控制菌毛蛋白Av的机制对于了解淋球菌疾病发病机制的这一方面至关重要。这项建议将继续我们的遗传学研究的分子机制，使菌毛Av。有两个具体目标：目的1将继续我们的基因和蛋白质产物的鉴定和表征，揭示了遗传筛选，参与介导和调节菌毛蛋白抗原变异。 目的2将探讨菌毛蛋白抗原变异的机制，通过定义保守的DNA序列在菌毛蛋白抗原变异中的作用，通过测试解释菌毛蛋白抗原变异的新模型，通过定义如何维持菌毛蛋白变异的可变性，并通过重新检查一个有争议的假设，即DNA转化在介导菌毛蛋白Av中发挥作用。 这些研究的结果将有助于维持菌毛蛋白抗原变异作为基于基因组易位的系统的主要原核范例之一，并进一步了解DNA重组如何成为微生物致病的重要机制。

DESCRIPTION (provided by applicant): The Gram-negative bacterium, Neisseria gonorrhoeae, is the only causative agent of the sexually transmitted disease gonorrhea. One important facet of gonococcal pathogenesis is the process of pilin antigenic variation (Av), which allows for immune evasion by the bacterium and continual retransmission through the high risk/core group of infected people. In addition, the pilus functions in the initiating events of colonization and the functional properties of the pilus can be altered by pilin antigenic variation. Understanding the mechanisms used to effect and control pilin Av is essential to understanding this aspect of the pathogenesis of gonococcal disease. This proposal will continue our genetic studies into the molecular mechanisms used to enable pilin Av. There are two specific aims: Aim 1 will continue our identification and characterization of genes and protein products, revealed by a genetic screen, that are involved in mediating and regulating pilin antigenic variation. Aim 2 will explore the mechanisms of pilin antigenic variation by defining the role of conserved DNA sequences in pilin antigenic variation, by testing novel models that explain pilin antigenic variation, by defining how variability of pilin variation is maintained, and by re-examining a controversial hypothesis that DNA transformation has a role in mediating pilin Av. The results from these studies will help maintain pilin antigenic variation as one of the main prokaryotic paradigms for systems based on genomic translocations, and further our understanding of how DNA recombination can be central to an important mechanism of microbial pathogenesis.