Bacillus subtilis stress responses

项目总结/摘要 细菌和人类有着复杂的关系：我们丰富的浮游生物提供了 细菌具有许多益处，而致病性细菌造成了发病率和死亡率的巨大负担。的 免疫系统通过营养免疫、抗微生物肽、溶解酶 和吞噬细胞。潜在的病原体通过激活特定的适应性细胞来应对这些威胁。 反应，其中许多对毒力至关重要。我们研究了枯草芽孢杆菌的应激反应， 革兰氏阳性菌。其中一个项目涉及对不断变化的必需营养素供应的反应 金属离子锌、铁和锰。免疫系统通过金属限制病原体的生长 在组织中（例如通过钙卫蛋白）和吞噬作用后的隔离。此外，吞噬细胞杀死 金属中毒的细胞我们已经证明，金属离子的稳态依赖于特定的金属传感 对铁（Fur和PerR）、锰（MntR）和锌的限制和过量应答的转录因子 (Zur和CzrA）。我们将描述由这些转录因子调控的基因，它们在金属代谢中的作用， 体内平衡，并确定由金属离子限制和中毒引起的生理效应。 这项工作将建立在我们最近确定的铁和锰的主要外排系统。的 这些研究的见解将直接与人类存在的类似压力反应有关。 病原体免疫系统还通过产生抗菌肽来限制病原体的生长 和溶解酶，两者都影响细胞被膜的完整性。细胞包膜也是 许多最重要的抗生素在第二个项目中，我们定义了几个不同的细胞包络 B的应激反应。枯草芽孢杆菌，重点是那些由替代西格玛因素调节。我们已经确定 一系列在应激反应途径和关键中枢代谢途径中发生改变的突变体， 对细胞壁抗生素的敏感性增加，包括至关重要的β-内酰胺。另外我们 探索新发现的抗生素协同作用，可能对临床方法产生影响。选择 抗生素抗性抑制剂提供了一种描述抗生素协同作用基础的强有力的方法， 以及特定应激反应途径的作用。这些通路是细胞包膜稳态的中心 一般来说，除了它们在感知和响应植物诱导的应激中的作用外， 病原体中抗生素耐受性和耐药性的出现。

Project Summary/Abstract Bacteria and humans have a complex relationship: our abundant commensal organisms provide numerous benefits, whereas pathogenic bacteria impose a large burden of morbidity and mortality. The immune system restricts bacterial growth through nutritional immunity, antimicrobial peptides, lytic enzymes, and phagocytic cells. Potential pathogens respond to these threats by the activation of specific adaptive responses, many of which are critical for virulence. We study stress responses in Bacillus subtilis, a model Gram positive bacterium. One project addresses responses to the changing availability of the essential nutrient metal ions zinc, iron, and manganese. The immune system restricts the growth of pathogens by metal sequestration, both in tissues (e.g. by calprotectin) and after phagocytosis. In addition, phagocytic cells kill cells by metal intoxication. We have demonstrated that metal ion homeostasis relies on specific metal-sensing transcription factors that respond to limitation and excess of iron (Fur and PerR), manganese (MntR), and zinc (Zur and CzrA). We will characterize the genes regulated by these transcription factors, their roles in metal homeostasis, and identify the physiological effects that result from both metal ion limitation and intoxication. This work will build upon our recent identification of the major efflux systems for both iron and manganese. The insights from these studies will be directly relevant to the similar stress responses present in human pathogens. The immune system also restricts the growth of pathogens by production of antibacterial peptides and lytic enzymes, both of which affect the integrity of the cell envelope. The cell envelope is also a target for many of our most important antibiotics. In a second project, we have defined several distinct cell envelope stress responses in B. subtilis, with a focus on those regulated by alternative sigma factors. We have identified an array of mutants with alterations in stress response pathways and in key central metabolic pathways that have elevated sensitivity to cell wall antibiotics, including the critically important beta-lactams. In addition, we explore newly discovered antibiotic synergies with possible implications for clinical approaches. Selection of antibiotic resistant suppressors provides a powerful approach for delineating the basis of antibiotic synergies, and the roles of specific stress response pathways. These pathways are central to cell envelope homeostasis generally, in addition to their role in sensing and responding to antibiotic-induced stress, and are implicated in the emergence of antibiotic tolerance and resistance in pathogens.