Pseudomonas aeruginosa quorum sensing

铜绿假单胞菌群体感应

基本信息

批准号：
10319599
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-05 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319599
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 Persons Plague Population Population Control Production Pseudomonas aeruginosa Pseudomonas aeruginosa infection Pulmonary Cystic Fibrosis Regulation Regulon Reporting Respiratory Tract Infections 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

项目摘要

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.

项目摘要群体灵敏度（QS）是细菌使用的广泛分布的细胞间通信方法协调小组活动。机会性人类病原体假单胞菌使用QS来调节生产许多分泌产品，包括病毒因子，抗生素和蛋白酶。铜绿假单胞菌改变其行为作为一组的能力有助于治疗这种细菌囊性纤维化等疾病，在其中建立了慢性气道感染。在铜绿假单胞菌中，QS是部分由转录因子LASR和RHLR介导的，它们对酰基 - 双叶酮内酯反应信号。在实验室菌株中，LASR调节RHLR，并共同控制了数百个的转录基因。 LASR突变体在CF中很常见（尽管通常不会观察到RHLR突变体）表示这些分离株中QS的灭活。但是，在许多铜绿假单胞菌中分离出来的囊性纤维化，RHLR活性不依赖LASR，许多LASR无效分离株仍然参与酰基 - 耶洛舍碱内酯QS。这些菌株中有源RHLR QS的存在意味着QS对于调节某些人很重要 CF肺中的因素。该建议使用大量的铜绿假单胞菌分离株从囊性纤维化中探索适应的患者铜绿假单胞菌为保存QS目的地LASR突变而制作。实验在本提案中描述：1）QS转录因子调节的基因是什么？临床分离株的“核心” QS常规； 2）允许独立于LASR的RHR的遗传变化是什么这些临床分离株的激活，RHR的直接基因靶标是什么？ 3）什么是防止铜绿假单胞菌种群出现RHL突变体的分子机制？这些问题的答案将为临床P.铜绿杂志提供更完整的QS图表，并指南旨在靶向QS或QS调节的基因来管理和治疗人类疾病中细菌群体的努力。