Modulation of Virulence Determinants Contributing to Gonococcal Pathogenesis

描述（由申请人提供）：淋病奈瑟菌是一种革兰氏阴性，严格的人类病原体，导致性传播疾病，淋病。全球淋病感染的发病率（估计每年超过6000万例）以及细菌对用于治疗感染的大多数抗生素产生耐药性的能力使其成为全球公共卫生问题。淋球菌感染通常起始于粘膜表面，并且需要细菌与上皮细胞的相互作用。淋球菌附着于粘膜表面的主要介质之一是IV型pil（Tfp），它是从细菌延伸并与上皮细胞上的受体相互作用的菌毛蛋白聚合物。本研究的目的是明确N.淋病编码主要菌毛蛋白亚基（PilE）的基因受到相位和抗原性变化的影响。我们最近已经确定了一个转录调控因子PssR（菌毛分泌系统阻遏蛋白），负调控菌毛生物合成操纵子（pilMNOPQ）和发散转录青霉素结合蛋白1（ponA）以及基因（rdgC），编码的蛋白质参与菌毛抗原变异。此外，我们的初步数据表明，PssR调控基因表达的N。淋病可能用于调节细菌对先天宿主防御机制的易感性水平，特别是阳离子抗菌肽，该阳离子抗菌肽被认为在宿主抵抗感染中是重要的。为了更好地定义PssR的调控特性，我们将确定其DNA结合和转录调控特性（具体目标1）。我们还将确定与抗微生物剂毒力和耐药性相关的PssR缺失或过度表达的表型效应（具体目标2）。由于TFP是启动感染的泌尿生殖道粘膜表面的关键，研究TFP和/或其他毒力决定因素的调节将推进我们的知识淋球菌如何调节毒力决定因素，以及它们的调节如何有助于发病机制。

DESCRIPTION (provided by applicant): Neisseria gonorrhoeae is a Gram-negative, strict human pathogen that causes the sexually transmitted disease, gonorrhea. The incidence of gonorrhea infections worldwide (estimated at over 60 million cases a year) and the ability of the bacteria to become resistant to most antibiotics used to treat infections makes it a global public health concern. Gonoccocal infections are usually initiated on mucosal surfaces, and require interaction of the bacteria with epithelial cells. One of the primary mediators of gonococcal attachment to mucosal surfaces is the Type IV pil (Tfp), which are polymers of pilin that extend from the bacteria and interact with receptors on epithelial cells. The goal of the proposed research is to define the regulatory mechanisms that control expression of Tfp in N. gonorrhoeae. The gene encoding the major pilin subunit (PilE) is subject to both phase and antigenic variation. We recently have identified a transcriptional regulator termed PssR (Pilus secretion system Represser Protein) that negatively regulates the pilus biosynthesis operon (pilMNOPQ) and the divergently transcribed penicillin-binding protein 1 (ponA) as well as a gene (rdgC) that encodes a protein involved in pilin antigenic variation. Moreover, our preliminary data indicate that PssR regulation of gene expression in N. gonorrhoeae may serve to modulate levels of bacterial susceptibility to innate host defense mechanisms, in particular the cationic antibacterial peptides that are postulated to be important in host resistance to infection. In order to better define the regulatory properties of PssR, we will determine its DNA-binding and transcriptional regulatory properties (Specific Aim 1). We will also determine the phenotypic effects of loss or over-expression of PssR relating to virulence and resistance to antimicrobials (Specific Aim 2). Since Tfp are critical for initiation of infection on mucosal surfaces of the genitourinary tract, studies on regulation of Tfp and/or other virulence determinants will advance our knowledge of how gonococci regulate virulence determinants and how their regulation contributes to pathogenesis.