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

描述（由申请方提供）：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。它随后激活调节细胞对感染反应的信号通路。附着由静态Tfp纤维介导。信号传导需要通过收缩纤维施加在定殖细胞上的物理力。我们的初步研究结果表明，TFP的直肠奈瑟菌也介导的附件。然而，细菌性和致病性奈瑟氏菌Tfp的生物学在两个主要方面不同。1)Tfp基因编码的附着和收缩组件是在不同的转录调控。2)Tfp回缩激活上皮细胞内不同的信号级联。我们假设Tfp是一个开关，决定是否奈瑟菌定植导致非典型肺炎（无症状定植）或发病机制。这类似于交叉路口的铁路道岔，将火车（细菌）引导到通往不同目的地的轨道上（寄生虫病或发病机制）。我们进一步假设Tfp开关机制由两个关键组成部分组成：其机制基因的转录调控和其上皮细胞信号传导活动。转录调控决定何时和 其中发生Tfp介导的附着和收缩。在宿主细胞中激活的信号级联的类型决定了定殖的结果。我们提出了两个目标来检验这一假设。

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.