Mechanisms of Pheromone-Controlled Lysozyme Resistance and Surface Display of Streptococcus pyogenes

化脓性链球菌信息素控制的溶菌酶抗性和表面展示机制

• 批准号: 10054149
• 负责人: MICHAEL J FEDERLE
• 金额: $ 39.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054149
• 关键词: Accounting; Adhesives; Affect; Amidohydrolases; Aminoglycosides; Animal Model; Antibiotics; Appearance; Bacteria; Bacterial Adhesins; Behavior; Beta-N-Acetylglucosaminidase; Binding; Biochemical; Cell Aggregation; Cell Wall; Cell surface; Cells; Chemicals; Communicable Diseases; Communication; Communities; Cysteine; Cytokine Signaling; Data; Development; Disease Outbreaks; Enzyme Inhibitor Drugs; Enzymes; Epithelial Cells; Fibronectins; Histidine; Human body; Hydrolase; Hydrophobicity; Immune; Immune response; Immunologic Surveillance; Invaded; Lead; Life Style; Mediating; Microbial Biofilms; Muramidase; N-Acetylmuramoyl-L-alanine Amidase; Nutrient; Pathway interactions; Peptide Hydrolases; Peptides; Peptidoglycan; Perception; Periodicity; Phenotype; Pheromone; Pheromone Receptors; Physiological; Predisposition; Production; Property; Proteins; Recombinant Proteins; Regulation; Regulatory Pathway; Resistance; Signal Transduction; Streptococcus pyogenes; Structural Protein; Surface; Testing; Therapeutic; Toxin; Virulent; experimental study; host colonization; immunoregulation; in vivo; pathogen; pathogenic bacteria; quorum sensing; small molecule; social

Project Summary/Abstract Little is understood about the physiological or regulatory factors of Streptococcus pyogenes that enable switching between its commensal-like and virulent states. This proposal describes experimental approaches that seek to continue defining and characterizing quorum-sensing regulatory pathways that correspond to phenotypes consistent with the avirulent lifestyle of Streptococcus pyogenes (Group A Streptococcus; GAS). The quorum sensing network in Streptococcus pyogenes utilizing short hydrophobic peptide (SHP) pheromones and the pheromone receptors Rgg2 and Rgg3 regulates several phenotypes, including biofilm development, cell aggregation, aminoglycoside susceptibility, and lysozyme resistance, by an unknown mechanism. Our studies indicate that each of these phenotypes depend upon the expression of a small protein of unknown function. We hypothesize that this protein, referred to as StcB, is an inhibitor of an enzyme(s) that targets peptidoglycan bonds of the cell wall. Additional studies indicate the target of StcB is a murein hydrolase enzyme, called Isp, that contains cysteine and histidine-dependent amidohydrolase/peptidase (CHAP) and acetylglucosaminidase domains. Governance of StcB and Isp by the Rgg2/3 quorum sensing pathway accounts for significant changes to the bacterial cell surface, resulting in differential attachment to fibronectin and epithelial cells, and differential immuno- modulatory activities. This proposal seeks to elucidate the mechanisms by which StcB and Isp enzymes account for biochemical changes to the surface of S. pyogenes, how these changes lead to differential activity of surface structures and proteins, and how these changes affect the ability of S. pyogenes to colonize the host and modulate immune activities.

项目摘要/摘要 对化脓性链球菌的生理或调节因子了解甚少。 使其能够在类共生状态和毒力状态之间切换。这份提案描述了 寻求继续定义和表征群体感应的实验方法 与无毒生活方式一致的表型对应的调控途径 化脓性链球菌(A组；GAS)。中的仲裁感测网络 利用短疏水肽信息素和信息素的化脓性链球菌 受体Rgg2和Rgg3调节几种表型，包括生物膜发育、细胞 聚集、氨基糖苷类药物敏感性和溶菌酶耐药性，其机制未知。 我们的研究表明，这些表型中的每一种都依赖于一种小蛋白的表达 未知函数。我们假设这种被称为StcB的蛋白质是一种 以细胞壁的肽聚糖为靶标的酶(S)。更多研究表明， StcB是一种叫做isp的乳清蛋白水解酶，它含有半胱氨酸和依赖组氨酸的物质。 氨基水解酶/肽酶(CHAP)和乙酰氨基葡萄糖苷酶结构域。科技园及互联网服务商的管治 通过Rgg2/3群体感应通路解释细菌细胞表面的显著变化， 导致与纤维连接蛋白和上皮细胞的不同黏附，以及不同的免疫 调节活动。本提案旨在阐明STcB和ISP通过什么机制 酶是化脓性链球菌表面生化变化的原因，这些变化是如何导致 表面结构和蛋白质的不同活性，以及这些变化如何影响S。 化脓性细菌能定植宿主并调节免疫活动。