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并对应激环境因素做出反应，以便将对细胞的伤害降至最低。我们建议研究一种新的途径，通过这种途径，细菌可以通过使用囊泡从细胞中移除有毒应激源，从而避免包膜压力的致命后果。外膜小泡为细菌提供了一种丢弃有毒的不溶性包膜物质的方法。小泡含有外膜和周质成分的子集。它们是结构性产生的，没有伴随的细菌裂解。囊泡在细菌病原体和真核细胞之间的毒力因子和免疫调节分子的运输中的作用是最新的特征。克服致命性应激源对于细胞的生存至关重要，但也应该考虑到，当应激反应促进细胞产物的分泌时，它会显著影响即刻和远端环境。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。对调控囊泡产生的分子和遗传基础知之甚少。我们的初步结果证明了由各种包膜因素触发的特定的应激诱导的囊泡产生。拟议的实验方法将是表征由大肠杆菌产生囊泡的分子触发因素，以 确定与应激诱导的囊泡产生相关的包膜变化的特征，并确定与应激相关的囊泡产生的遗传学基础。这项研究将对人类健康产生影响，因为研究结果将对理解这一与毒力因子传播和炎症相关的常见细菌病原体过程产生革命性的见解，并有可能发现新的细菌脆弱性，可用于药物治疗。 与公共卫生相关：外膜囊泡的产生影响细菌的生存，并允许炎症和毒力因子在紧张的宿主环境中传播。这项研究计划旨在改变人们对这种细菌对应激源反应的普遍理解。通过这些研究了解囊泡反应的机制将使我们能够帮助防止病原菌在世界范围内导致人类疾病。

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. PUBLIC HEALTH RELEVANCE: The generation of outer membrane vesicles impacts bacterial survival and allows the dissemination of inflammatory and virulence factors in the stressful host environment. This research plan is designed to transform the general understanding of this bacterial response to stressors. Understanding the mechanics of the vesiculation response through these studies will enable us to help prevent pathogenic bacteria from causing human disease worldwide.