Type IV pilus as a switch that determines consequences of Neisseria colonization

描述（由申请人提供）：IV型菌毛（Tfp）是一种毒力因子，介导致病性奈瑟菌与上皮细胞的初始接触。它随后激活信号通路，调节细胞对感染的反应。附着是由静态Tfp纤维介导的。信号传递需要通过收缩纤维对定植细胞施加物理力。我们的初步研究结果表明，共生奈瑟菌的Tfp也介导附着。然而，共生和致病性奈瑟菌Tfp的生物学特性在两个主要方面有所不同。1) Tfp基因编码的附着和缩回组分受到不同的转录调控。2) Tfp回缩激活上皮细胞中不同的信号级联反应。我们假设Tfp是一个开关，决定奈瑟菌定植是否导致共生（无症状定植）或发病机制。这类似于一个铁路交汇处的开关，它引导火车（细菌）沿着通往不同目的地的轨道（共生或发病机制）。我们进一步假设Tfp开关机制由两个关键组成部分组成：其机械基因的转录调控及其上皮细胞信号传导活动。转录调控决定何时和何时

DESCRIPTION (provided by applicant): The Type IV pilus (Tfp) is a virulence factor that mediates the initial contact of pathogenic Neisseria with epithelial cells. It subsequently activates signaling pathways that modulate cellular responses to infection. Attachment is mediated by static Tfp fibers. Signaling requires physical force exerted on the colonized cell by retracting fibers. Our preliminary findings indicate Tfp of commensal Neisseria also mediates attachment. However, the biology of commensal and pathogenic Neisseria Tfp differs in two major respects. 1) Tfp genes encoding the attachment and retraction components are under different transcriptional regulation. 2) Tfp retraction activates different signaling cascades in te epithelial cell. We hypothesize Tfp is a switch that determines whether Neisseria colonization leads to commensalism (asymptomatic colonization) or pathogenesis. This is analogous to a railroad switch at a junction that directs a train (bacterium) down tracks leading to different destinations (commensalism or pathogenesis). We further hypothesize the Tfp switching mechanism consists of two critical components: transcriptional regulation of its machinery genes, and its epithelial cell signaling activities. Transcriptional regulation determines when and where Tfp-mediated attachment and retraction occur. The types of signaling cascades activated in the host cell determine the outcome of colonization. We propose two Aims to test this hypothesis.