Modulation of Virulence Determinants Contributing to Gonococcal Pathogenesis

调节导致淋球菌发病机制的毒力决定因素

• 批准号: 7498245
• 负责人: Daniel Williams
• 金额: $ 9.72万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7498245
• 关键词: Anabolism; Anti-Bacterial Agents; Antibiotics; Antigenic Variation; Antimicrobial Resistance; Bacteria; Binding; Biogenesis; Biological; Biological Assay; Biological Process; Cells; Complex; DNA Binding; Data; Deoxyribonuclease I; Epithelial; Epithelial Cells; Epithelium; Eye; Fimbriae Proteins; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genitourinary system; Goals; Gonorrhea; Host Defense Mechanism; Host resistance; Human; Immune; Incidence; Infection; Knowledge; Measurement; Mediating; Mediator of activation protein; Membrane; Neisseria gonorrhoeae; Open Reading Frames; Operon; Pathogenesis; Penicillin Binding Protein 1; Peptides; Pharyngeal structure; Phase; Pilum; Polymers; Predisposition; Property; Proteins; Public Health; Rectum; Regulation; Reporter Genes; Research; Resistance; Resistance to infection; Reverse Transcriptase Polymerase Chain Reaction; Sexually Transmitted Diseases; Site; Surface; System; Thinking; Tissues; Transcript; Transcriptional Regulation; Variant; Virulence; antimicrobial peptide; conjunctiva; genome sequencing; mutant; pathogen; pathogenic bacteria; promoter; receptor; research study

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.

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，引起性传播疾病淋病。全世界淋病感染的发病率（估计每年超过6000万例）以及淋病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一个全球公共卫生问题。淋球菌感染通常始于粘膜表面，需要细菌与上皮细胞相互作用。淋球菌附着于粘膜表面的主要介质之一是IV型pil (Tfp)，它是从细菌延伸出来的pilin聚合物，并与上皮细胞上的受体相互作用。提出的研究目标是确定控制淋病奈瑟菌Tfp表达的调控机制。编码毛蛋白主要亚基（PilE）的基因受期变异和抗原变异的影响。我们最近发现了一种名为PssR（毛菌分泌系统抑制蛋白）的转录调节因子，它负调控毛菌生物合成操纵子（pilMNOPQ）和分散转录的青霉素结合蛋白1 (ponA)，以及编码参与毛菌抗原变异的蛋白质的基因（rdgC）。此外，我们的初步数据表明，PssR对淋病奈瑟菌基因表达的调控可能有助于调节细菌对先天宿主防御机制的易感性水平，特别是在宿主抗感染中被认为是重要的阳离子抗菌肽。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（Specific Aim 1）。我们还将确定与抗菌素毒力和耐药性相关的PssR缺失或过表达的表型效应（Specific Aim 2）。由于Tfp对泌尿生殖道粘膜表面感染的启动至关重要，对Tfp和/或其他毒力决定因素的调控研究将推进我们对淋球菌如何调控毒力决定因素及其调控如何促进发病机制的认识。