Mechanisms of Gonococcal Pilin Antigenic/Phase Variation

描述（由申请人提供）：革兰氏阴性菌淋病奈瑟菌是淋病的唯一病原体。淋球菌发病机制的一个重要方面是皮林抗原变异（Av）过程，该过程允许细菌逃避免疫，并通过高风险/核心感染者群体不断重新传播。此外，菌毛在定殖起始事件中起作用，菌毛的功能特性可因菌毛蛋白抗原变异而改变。了解用于影响和控制匹林Av的机制对于理解淋球菌病的这方面发病机制至关重要。该提案将继续我们的遗传学研究，用于使匹林Av的分子机制。有两个具体目标：Aim 1将继续我们的基因和蛋白质产物的鉴定和表征，通过遗传筛选揭示，参与介导和调节匹林抗原变异。Aim 2将通过定义保守DNA序列在匹林抗原变异中的作用，通过测试解释匹林抗原变异的新模型，通过定义匹林变异的可变性是如何维持的，来探索匹林抗原变异的机制。这些研究的结果将有助于维持匹林抗原变异作为基于基因组易位系统的主要原核生物范式之一，并进一步了解DNA重组如何成为微生物发病机制的核心。

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.