Bacillus subtilis Stress Responses

枯草芽孢杆菌应激反应

基本信息

批准号：
9903389
负责人：
John D Helmann
金额：
$ 77.52万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903389
关键词：
Acclimatization Address Affect Anti-Bacterial Agents Antibiotic Resistance Antibiotics Bacillus subtilis Bacteria Biological Models Cell Wall Cells Complex Environment Enzymes Genes Gram-Positive Bacteria Growth Homeostasis Human Immune system Innate Immune System Intoxication Invaded Ions Iron Leukocyte L1 Antigen Complex LytA enzyme Manganese Metals Modeling Morbidity - disease rate Mutation Nutrient Nutritional Immunity Organism Pathway interactions Peptides Periodicity Phagocytes Phagocytosis Phosphoric Monoester Hydrolases Phosphotransferases Physiological Production Role Second Messenger Systems Sigma Factor Stress System Tissues Virulence Work Zinc antibiotic tolerance antimicrobial peptide beta-Lactams biological adaptation to stress cell envelope cell killing human pathogen insight mortality pathogen pathogenic bacteria response transcription factor

项目摘要

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.

项目概要/摘要细菌和人类有着复杂的关系：我们丰富的共生生物提供了许多好处，而致病菌却造成了巨大的发病负担死亡。免疫系统通过营养免疫、抗菌作用来限制细菌生长肽、裂解酶和吞噬细胞。潜在的病原体通过以下方式应对这些威胁激活特定的适应性反应，其中许多对于毒力至关重要。我们研究压力枯草芽孢杆菌（一种模型革兰氏阳性细菌）的反应。一个项目解决了以下问题的回应：必需营养金属离子锌、铁和锰的可用性发生变化。免疫系统通过组织中的金属螯合（例如通过钙卫蛋白）来限制病原体的生长以及吞噬作用后。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稳态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 CzrA）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及其在金属中的作用稳态，并确定金属离子限制和中毒。这项工作将建立在我们最近确定的铁和铁的主要流出系统的基础上和锰。这些研究的见解将与类似的压力直接相关人类病原体中存在的反应。免疫系统还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。细胞包膜也是许多最重要抗生素的靶标。一秒钟项目中，我们在枯草芽孢杆菌中定义了几种不同的细胞包膜应激反应，重点是那些受细胞质外功能西格玛因子调节的细胞。我们将调查以下人员的贡献由抗生素诱导的 sigma-M 转录因子激活的基因以维持细胞包膜稳态，更具体地说是适应抗生素。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。细胞具有这些应激反应途径中的突变对细胞壁抗生素（例如β-内酰胺）敏感。抗生素耐药性抑制因子的选择提供了一种强有力的方法来描述这些响应途径及其相互关系。这些途径是细胞包膜的核心除了在感知和响应抗生素引起的应激方面的作用外，一般还具有体内平衡的作用，并与病原体抗生素耐受性和耐药性的出现有关。