Triggers and Consequences of Bacterial Envelope Stress

细菌包膜应激的触发因素和后果

• 批准号: 8629770
• 负责人: META J KUEHN
• 金额: $ 28.66万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629770
• 关键词: Affect; Architecture; Bacteria; Caliber; Cell secretion; Cells; Chimeric Proteins; Cytolysis; Data; Distal; Environment; Environmental Risk Factor; Escherichia coli; Eukaryotic Cell; Generations; Genetic; Goals; Gram-Negative Bacteria; Health; Human; Infection; Inflammation; Inflammatory; Lead; Mechanics; Mediating; Membrane; Membrane Proteins; Molecular; Molecular Chaperones; Molecular Genetics; Pathogenesis; Pathogenicity; Pathway interactions; Pharmacologic Substance; Phenotype; Process; Production; Property; Protein Overexpression; Proteins; Pseudomonas aeruginosa; Research; Role; Salmonella; Signal Transduction; Stress; Structure; Toxin; Vesicle; Virulence; Virulence Factors; antimicrobial; base; biological adaptation to stress; cell type; cytokine; design; env Gene Products; fitness; genetic analysis; human disease; insight; mutant; novel; overexpression; pathogen; pathogenic bacteria; periplasm; prevent; response; stressor; tool; trafficking; transmission process

DESCRIPTION (provided by applicant): All types of cells sense and respond to stressful environmental factors in order to minimize harm to the cell. We propose to investigate a novel pathway by which bacteria avoid lethal consequences of envelope stress by removing toxic stressors from the cell using vesicles. Outer membrane vesicles offer a means for bacteria to discard toxic insoluble envelope material. Vesicles contain a subset of outer membrane and periplasmic components. They are produced constitutively and without concomitant bacterial lysis. Vesicles have been most recently characterized for their roles in trafficking of virulence factors and immunomodulatory molecules between bacterial pathogens and eukaryotic cells. Overcoming lethal stressors is essential for cellular viability, but it should also be considered that when the stress response promotes secretion of cellular products, it significantly impacts the immediate and distal environment. The overall hypothesis of this study is that Gram-negative bacterial envelope stressors trigger outer membrane vesicle production, thereby modulating virulence properties of pathogens. Little is understood about the molecular and genetic basis regulating vesicle production. Our preliminary results demonstrate specific stress-induced vesicle production triggered by a variety of envelope factors. The proposed experimental approach will be to characterize the molecular triggers of vesiculation by E. coli, to characterize the envelope changes associated with stress-induced vesicle production, and to identify the genetic basis for stress- related vesicle production. This research will impact on human health because the results will yield transformative insight into the understanding of this common bacterial pathogen process associated with virulence factor transmission and inflammation, and potentially uncover new bacterial vulnerabilities that can be exploited with pharmaceutical treatment.

描述（由申请人提供）：所有类型的细胞都会感知并响应应激环境因素，以尽量减少对细胞的伤害。我们建议研究一种新的途径，通过该途径，细菌通过使用囊泡从细胞中去除有毒应激源来避免包膜应激的致命后果。外膜囊泡为细菌提供了一种丢弃有毒的不溶性包膜材料的方法。囊泡含有一部分外膜和周质成分。它们是组成型产生的并且没有伴随的细菌裂解。最近，囊泡因其在细菌病原体和真核细胞之间毒力因子和免疫调节分子运输中的作用而被表征。克服致命的应激源对于细胞的生存能力至关重要，但也应该考虑到，当应激反应促进细胞产物的分泌时，它会显着影响直接和远端的环境。这项研究的总体假设是革兰氏阴性细菌包膜应激源触发外膜囊泡的产生，从而调节病原体的毒力特性。人们对调节囊泡产生的分子和遗传基础知之甚少。我们的初步结果表明，特定的应激诱导的囊泡产生是由各种包膜因素触发的。所提出的实验方法将是表征大肠杆菌水泡形成的分子触发因素，以 表征与应激诱导的囊泡产生相关的包膜变化，并确定应激相关囊泡产生的遗传基础。这项研究将对人类健康产生影响，因为其结果将为理解这种与毒力因子传播和炎症相关的常见细菌病原体过程提供变革性的见解，并有可能发现可用于药物治疗的新细菌脆弱性。