Bacillus subtilis stress responses

项目摘要/摘要 细菌和人类有着复杂的关系：我们丰富的共生生物体提供了 许多好处，而致病菌造成了很大的发病率和死亡率负担。这个 免疫系统通过营养免疫、抗菌肽、裂解酶、 和吞噬细胞。潜在病原体对这些威胁的反应是通过激活特定的适应性 反应，其中许多对致病力至关重要。我们研究了枯草芽孢杆菌的应激反应，一个模型 革兰氏阳性菌。一个项目涉及对基本营养素可获得性变化的反应 金属离子锌、铁和锰。免疫系统通过金属来限制病原体的生长 在组织中的隔离(例如通过钙保护素)和吞噬后的隔离。此外，吞噬细胞杀死 细胞因金属中毒而死亡。我们已经证明了金属离子的动态平衡依赖于特定的金属传感。 对铁(Fur和Perr)、锰(MntR)和锌的限制和过量做出反应的转录因子 (祖尔和捷克)。我们将描述这些转录因子调控的基因，以及它们在金属中的作用 动态平衡，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流系统的基础上。这个 这些研究的洞察力将直接与人类存在的类似应激反应相关 病原体。免疫系统还通过产生抗菌肽来限制病原体的生长。 和裂解酶，这两者都会影响细胞被膜的完整性。单元格包络也是 我们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单元格包络 枯草杆菌的应激反应，重点是那些受替代西格玛因子调控的应激反应。我们已经确定了 一系列在应激反应途径和关键的中央代谢途径中发生变化的突变 对细胞壁抗生素，包括至关重要的β-内酰胺类抗生素的敏感度提高。此外，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。精选 抗生素耐药抑制物为描绘抗生素协同作用的基础提供了一种强有力的方法， 以及特定应激反应通路的作用。这些途径是细胞包膜动态平衡的中心 一般来说，除了它们在感知和响应抗生素诱导的应激反应中的作用外，还与 病原菌对抗生素的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.