Bacillus subtilis Stress Responses

项目摘要/摘要 细菌和人类有着复杂的关系：我们丰富的共生有机体 提供了许多好处，而致病菌造成了很大的发病率和负担 死亡率。免疫系统通过营养免疫、抗菌药物来限制细菌的生长 多肽、裂解酶和吞噬细胞。潜在的病原体对这些威胁的反应是 激活特定的适应性反应，其中许多对毒力至关重要。我们研究压力 模式革兰氏阳性菌枯草芽孢杆菌的反应。一个项目解决了对 必需的营养金属离子锌、铁和锰的有效性的变化。免疫者 系统通过金属隔离来限制病原体的生长，在组织中(例如通过钙保护素) 吞噬后。此外，吞噬细胞通过金属中毒杀死细胞。我们有 证明金属离子的动态平衡依赖于特定的金属感应转录因子 对铁(Fur和Perr)、锰(MntR)和锌(Zur和ChurA)的限制和过量做出反应。 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 喝醉了。这项工作将建立在我们最近确定的两种铁的主要外流系统的基础上 还有锰。这些研究的洞察力将与类似的压力直接相关 存在于人类病原体中的反应。免疫系统也会限制病原体的生长。 通过产生抗菌肽和裂解酶，这两者都会影响细胞的完整性 信封。细胞膜也是我们许多最重要的抗生素的靶标。一秒钟内 项目中，我们已经在枯草杆菌中定义了几种不同的细胞膜应激反应，重点是 那些受胞质外功能西格玛因子调控的基因。我们将调查以下方面的贡献 由抗生素诱导的Sigma-M转录因子激活的基因，使细胞包膜动态平衡， 更具体地说，就是适应抗生素。同时，我们将研究细胞壁的作用 应激反应激酶/磷酸酶系统和第二信使环二AMP。单元格带有 这些应激反应通路中的突变对细胞壁抗生素(如β-内酰胺类)敏感。 抗生素耐药抑制基因的选择为描述这些提供了一种有效的方法 反应途径及其相互联系。这些通路是细胞膜的中心 一般来说，除了在感知和响应抗生素诱导的应激反应中发挥作用外，体内平衡， 并与病原体对抗生素的耐受性和耐药性的出现有关。

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 extracytoplasmic function sigma factors. We will investigate the contributions of genes activated by the antibiotic-inducible sigma-M transcription factor to cell envelope homeostasis, and more specifically to acclimation to antibiotics. In parallel, we will examine the role of a cell wall stress responsive kinase/phosphatase system and the second messenger cyclic-di-AMP. Cells with mutations in these stress response pathways are sensitive to cell wall antibiotics (e.g. beta-lactams). Selection of antibiotic resistant suppressors provides a powerful approach for delineating these responsive pathways and their interconnections. 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.