Bacillus subtilis Stress Responses

枯草芽孢杆菌应激反应

• 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
• 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

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.

项目摘要/摘要 细菌和人类具有复杂的关系：我们丰富的共生生物 提供许多好处，而致病细菌会造成很大的发病率负担 死亡。免疫系统通过营养免疫，抗菌素限制细菌生长 肽，裂解酶和吞噬细胞。潜在的病原体应对这些威胁 特定自适应反应的激活，其中许多对毒力至关重要。我们研究压力 枯草芽孢杆菌的反应，一种模型革兰氏阳性细菌。一个项目解决了对 必需营养金属离子锌，铁和锰的可用性变化。免疫 系统在组织中都限制了金属隔离的病原体的生长（例如，通过钙蛋白钙蛋白酶） 并在吞噬作用后。另外，吞噬细胞通过金属醉酒杀死细胞。我们有 证明金属离子稳态取决于特定的金属感应转录因子 响应铁（皮草和perr），锰（MNTR）和锌（Zur和Czra）的限制和过量。 我们将表征由这些转录因子调节的基因，它们在金属中的作用 稳态，并确定金属离子限制和 中毒。这项工作将基于我们最近对两种铁的主要外排系统的识别 和锰。这些研究的见解将与类似的压力直接相关 人类病原体中的反应。免疫系统还限制了病原体的生长 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。细胞包膜也是我们许多最重要的抗生素的靶标。一秒钟 项目，我们在枯草芽孢杆菌中定义了几个不同的细胞包膜应力反应，重点是 由外质功能Sigma因子调节的人。我们将调查 通过抗生素诱导的Sigma-M转录因子激活细胞包膜稳态的基因， 更具体地适应抗生素。同时，我们将检查细胞壁的作用 应力响应激酶/磷酸酶系统和第二个信使环状-DI-AMP。带有细胞 这些应力反应途径中的突变对细胞壁抗生素（例如β-内酰胺）敏感。 选择抗生素抗性抑制剂为描述这些抑制作用提供了一种强大的方法 响应途径及其互连。这些途径是细胞包膜的核心 稳态通常，除了它们在感知和应对抗生素引起的压力方面的作用外， 并与病原体的抗生素耐受性和抗性有关。