Pseudomonas aeruginosa quorum sensing

铜绿假单胞菌群体感应

• 批准号: 10080743
• 负责人: Ajai Dandekar
• 金额: $ 31.1万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-05 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080743
• 关键词: Affinity; Antibiotics; Bacteria; Behavior; Biochemical; Biological; Biology; Cell Communication; Cell Density; Cells; Characteristics; Chronic; Clinical; Code; Collection; Communication Methods; Complex; Cooperative Behavior; Cystic Fibrosis; Data; Deterioration; Disease; Elements; Environment; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Diseases; Genome; Goals; In Vitro; Infection; Laboratories; Lung; Lung infections; Mediating; Modeling; Molecular; Morbidity - disease rate; Mutation; N-butyrylhomoserine lactone; Organism; Patients; Peptide Hydrolases; Plague; Population; Population Control; Production; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pulmonary Fibrosis; Regulation; Regulon; Reporting; Role; Signal Transduction; Source; System; Transcriptional Regulation; Virulence; Virulence Factors; Work; chronic infection; cystic fibrosis infection; cystic fibrosis patients; experimental study; homoserine lactone; human disease; human pathogen; intercellular communication; interest; mortality; mutant; opportunistic pathogen; preservation; prevent; quorum sensing; response; restraint; social; therapeutic development; transcription factor

Project Summary Quorum sensing (QS) is a broadly distributed intercellular communication method used by bacteria to coordinate group activities. The opportunistic human pathogen Pseudomonas aeruginosa uses QS to regulate the production of numerous secreted products that include virulence factors, antibiotics, and proteases. The ability of P. aeruginosa to alter its behavior as a group contributes to the difficulty of treating this bacterium in diseases such as cystic fibrosis, in which it establishes chronic airway infections. In P. aeruginosa, QS is mediated in part by the transcription factors LasR and RhlR, which respond to acyl-homoserine lactone signals. In laboratory strains, LasR regulates RhlR, and together they control the transcription of hundreds of genes. LasR mutants are common in CF (although RhlR mutants are not usually observed) implying inactivation of QS in these isolates. However, in many P. aeruginosa isolates from cystic fibrosis, RhlR activity is not dependent on LasR and many LasR-null isolates still engage in acyl-homoserine lactone QS. The presence of active RhlR QS in these strains implies that QS is important for the regulation of certain factors within the CF lung. This proposal uses a large collection of P. aeruginosa isolates from cystic fibrosis patients to explore adaptations P. aeruginosa makes to preserve QS despite lasR mutation. The experiments described in this proposal ask: 1) what are the genes regulated by QS transcription factors and what is the “core” QS regulon of clinical isolates; 2) what are the genetic changes that allow for LasR-independent RhlR activation in these clinical isolates and what are the direct gene targets of RhlR?; and 3) what are the molecular mechanisms that prevent RhlR mutants from emerging in populations of P. aeruginosa? The answers to these questions will give a more complete picture of QS in clinical P. aeruginosa, and guide efforts to target QS or QS-regulated genes to manage and treat bacterial populations in human disease.

项目概要 群体感应（QS）是一种广泛分布的细胞间通讯方法，细菌利用它来 协调小组活动。机会性人类病原体铜绿假单胞菌利用 QS 来调节 产生多种分泌产物，包括毒力因子、抗生素和蛋白酶。这 铜绿假单胞菌作为一个群体改变其行为的能力导致了治疗这种细菌的困难 囊性纤维化等疾病会导致慢性气道感染。在铜绿假单胞菌中，QS 是 部分由转录因子 LasR 和 RhlR 介导，它们对酰基高丝氨酸内酯有反应 信号。在实验室菌株中，LasR 调节 RhlR，它们共同控制数百个基因的转录 基因。 LasR 突变体在 CF 中很常见（尽管通常观察不到 RhlR 突变体），这意味着 这些分离株中 QS 失活。然而，在许多囊性纤维化铜绿假单胞菌中，RhlR 活性 不依赖于 LasR，并且许多 LasR 无效分离株仍参与酰基高丝氨酸内酯 QS。 这些菌株中活性 RhlR QS 的存在意味着 QS 对于调节某些 CF 肺内的因素。该提案使用大量从囊性纤维化中分离出来的铜绿假单胞菌 患者探索铜绿假单胞菌在 lasR 突变的情况下如何保持 QS。实验 该提案中描述的问题是：1）QS转录因子调控的基因是什么？ 临床分离株的“核心”QS调节子； 2) 哪些基因变化导致了 LasR 独立的 RhlR 这些临床分离株中的激活情况以及 RhlR 的直接基因靶标是什么？ 3）什么是 阻止铜绿假单胞菌群体中出现 RhlR 突变体的分子机制？ 这些问题的答案将更全面地描述临床铜绿假单胞菌的 QS，并指导 努力瞄准 QS 或 QS 调节的基因来管理和治疗人类疾病中的细菌群体。