Triggers and Consequences of Bacterial Envelope Stress

描述（由申请人提供）：所有类型的细胞都能感知和响应压力环境因素，以尽量减少对细胞的伤害。我们建议研究一种新的途径，通过这种途径，细菌可以利用囊泡从细胞中去除有毒的应激源，从而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物质的手段。囊泡包含外膜和质周成分的子集。它们是组成性生产的，没有伴随的细菌裂解。囊泡最近被描述为在细菌病原体和真核细胞之间运输毒力因子和免疫调节分子的角色。克服致死性应激源对细胞生存至关重要，但也应考虑到，当应激反应促进细胞产物的分泌时，它会显著影响直接和远端环境。本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。对调控囊泡产生的分子和遗传基础了解甚少。我们的初步结果表明，特定的应力诱导囊泡的产生是由多种包膜因子触发的。提出的实验方法将是表征大肠杆菌囊泡的分子触发因素

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.