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，介导致病性奈瑟氏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。附着是由静态的TFP纤维介导的。信号需要通过收缩纤维施加在定植的细胞上的物理力。我们的初步发现表明，共生奈瑟菌的TFP也起到了调节依恋的作用。然而，共生和致病奈瑟菌TFP的生物学在两个主要方面有所不同。1)编码附着和回缩成分的TFP基因受不同的转录调控。2)TFP回缩激活TE上皮细胞不同的信号级联反应。我们假设TFP是一个决定奈瑟氏菌定植是否导致共生(无症状定植)或致病的开关。这类似于交叉口的铁路道岔，它将列车(细菌)引向通往不同目的地的轨道(共生或致病)。我们进一步假设TFP转换机制由两个关键部分组成：其机械基因的转录调控和其上皮细胞的信号活动。转录调控决定了何时和 TFP介导的附着和回缩发生的地方。宿主细胞中激活的信号级联的类型决定了定植的结果。我们提出了两个目的来检验这一假设。

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.