Role of Neisseria Gcp in Tfp dynamics and invasion

描述（由申请人提供）：淋病奈瑟菌是一种人类病原体，可以在粘膜上持续很长时间而不会引起明显的疾病症状。临床和基础研究结果表明，症状性感染的发生可能是由于静止和毒性之间微妙平衡的转变。淋病奈瑟菌IV型菌毛（Tfp）在依恋的早期阶段起着重要作用。Tfp启动了细菌与宿主之间的多维通信系统，激活了降低宿主细胞毒性和提高宿主细胞存活率的信号通路。淋病奈瑟菌产生一种影响Tfp动态和侵袭的糖蛋白酶Gcp。gcp突变体产生大量的Tfp纤维束在一起，这些纤维束的收缩力比wt菌株大。突变体更具侵袭性，这意味着Gcp通常会降低毒力。我们将验证这些表型在机制上相关的假设，以及它们在Gcp加工/修饰pilin （Tfp结构亚基）和宿主细胞蛋白的基础上。本研究的总体目标是了解影响tfp介导感染的细胞生物学和生物物理学的因素，因为它们有可能破坏宿主和病原体之间的这种平衡。淋病奈瑟菌是一种性传播的人类病原体，可在粘膜表面持续很长时间而不引起明显的疾病。一些研究结果表明，有症状的淋球菌感染可能是由于在感染早期建立的静止和毒力之间的微妙平衡发生了变化。本提案的目的是确定neisserial糖蛋白酶（Gcp）如何通过其对细菌和宿主细胞蛋白的活性影响这种平衡。

DESCRIPTION (provided by applicant): Neisseria gonorrhoeae is a human pathogen that can persists on the mucosa for lengthy periods without causing overt symptoms of disease. Clinical and basic findings suggest that the onset of sympomatic infection may be due to a shift in the delicate balance between quiescence and virulence. The N. gonorrhoeae Type IV pilus (Tfp) plays a major role in the early stages of attachment. Tfp initiates a multi-dimensional communication system between the bacterium and the host, activating signaling pathways that reduce host cell toxicity and enhance host cell survival. N. gonorrhoeae produces a glycoprotease, Gcp, that affects Tfp dynamics and invasion. The gcp mutant produces Tfp fibers that bundle together in great numbers, and these bundles retract with higher force than the wt strain. The mutant is more invasive, implying that Gcp normally reduces virulence. We will test the hypothesis that these phenotypes are mechanistically related, and that they have their basis in Gcp processing/modification of pilin (the Tfp structural subunit) and host cell proteins. The overall goal of this study is to understand the factors that affect the cell biology and biophysics of Tfp-mediated infection, as they have the potential to disturb this balance between host and pathogen. Project Narrative Neisseria gonorrhoeae, a sexually transmitted pathogen of humans, can persist on the mucosal surface for lengthy periods without causing overt disease. Several findings suggest that symptomatic gonococcal infection may be due to a shift in the delicate balance between quiescence and virulence that had been established early in infection. The aim of this proposal is to determine how the neisserial glycoprotease, Gcp, affects this balance through its activity on bacterial and host cell proteins.