Bacterial responses to reactive chlorine stress and their role in host-microbe interactions

细菌对活性氯胁迫的反应及其在宿主-微生物相互作用中的作用

• 批准号: 10241451
• 负责人: Michael Jeffrey Gray
• 金额: $ 36.48万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241451
• 关键词: Affect; Animals; Anti-Inflammatory Agents; Bacteria; Biochemical; Cell Culture Techniques; Chloramines; Chlorine; DNA; Disease; Disinfectants; Environment; Epithelial; Escherichia coli; Gene Proteins; Genetic; Goals; Health; Home; Household; Human; Human Microbiome; Human body; Hypochlorous Acid; Immune system; Industrialization; Inflammation; Inflammatory; Innate Immune System; Intestines; Lactobacillus reuteri; Lead; Lipids; Mammalian Cell; Mediating; Medical; Microbe; Modeling; Molecular; Mucous Membrane; Organism; Oxidants; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Physiological; Play; Proteins; Reactive Oxygen Species; Regulator Genes; Research; Role; Specificity; Stress; Systems Biology; Techniques; Testing; Toxic effect; Toxin; Work; antimicrobial; biological adaptation to stress; cofactor; commensal bacteria; fighting; gut colonization; gut microbes; gut microbiota; host-microbe interactions; in vivo; microbiome; neutrophil; novel; pathogenic bacteria; programs; response; transcription factor; transcriptomics

Project Summary/Abstract The interface between bacteria and the immune system is absolutely fundamental to human health, and the long-term goal of my work is to understand how that interface is regulated. Colonization of the gut by both pathogenic and commensal bacteria has major effects on human health. Gut microbial communities are strongly affected by the redox environment of the intestine and by oxidants produced by the innate immune system during inflammation. These include both reactive oxygen species (ROS) and reactive chlorine species (RCS). RCS, including hypochlorous acid (HOCl) and reactive chloramines, are powerful antimicrobial oxidants capable of damaging many cellular components, including proteins, lipids, cofactors, and DNA. HOCl is a very common disinfectant in medical, industrial, and home settings, but RCS are also a natural part of the antimicrobial arsenal of neutrophils, accumulate during inflammation, and appear to be important for controlling bacterial colonization of mucosal epithelia, such as those in the gut. Little is known about how the bacteria which make up the human microbiome sense or respond to RCS, and this response is expected to be critical for the ability of bacteria to survive interactions with the human immune system. The research proposed in this application will use transcriptomic, genetic, biochemical, and systems biology techniques to identify and characterize the genes, proteins, and pathways which bacteria use to sense and respond to RCS, and will use mammalian cell culture and animal studies to test the roles of these mechanisms in host-microbe interactions. Our short- to medium-term goals focus on the gut microbes Escherichia coli and Lactobacillus reuteri. E. coli is physiologically very well characterized, easy to manipulate, and pro-inflammatory, while L. reuteri is anti- inflammatory and associated with a healthy microbiome. We will identify and characterize RCS-sensing regulators in these organisms and characterize the molecular mechanisms by which those regulators and the genes they control protect the bacteria against RCS-mediated damage and influence interactions between bacteria and their mammalian hosts. In the longer-term, these studies will be expanded to other model bacteria in order to characterize RCS responses across the diversity of the microbiome. The ultimate goal of this research is to understand RCS stress responses in medically important bacteria, particularly focusing on the roles they play in colonization and pathogenesis. The results of this research program will advance the field of oxidative stress response, elucidate the basis for the in vivo specificity of RCS-sensing transcription factors, help understand the underlying causes of RCS toxicity, and may lead to identification of novel mechanisms of interaction between bacteria and the innate immune system. This could potentially lead to new microbe-targeted treatments for the growing list of inflammatory diseases known to be influenced by the microbiome, and may have broad implications for our understanding of host-microbe interactions, pathogenesis, colonization, and RCS tolerance in a wide variety of organisms.

项目摘要/摘要 细菌与免疫系统之间的接口绝对是人类健康的基础， 我的工作的长期目标是了解该界面是如何调节的。肠道的殖民 致病性和共生细菌对人类健康有重大影响。肠道微生物群落是 受肠道氧化还原环境的强烈影响，并受到先天免疫产生的氧化剂的影响 炎症期间的系统。这些包括活性氧（ROS）和反应性氯种类 （RCS）。 RCS，包括次伐多酸（HOCL）和反应性氯胺，是强大的抗菌素 能够损害许多细胞成分的氧化剂，包括蛋白质，脂质，辅助因子和DNA。 HOCL 是医疗，工业和家庭环境中非常普遍的消毒剂，但RCS也是自然的一部分 中性粒细胞的抗菌砷，在炎症期间积聚，似乎对于控制很重要 粘膜上皮的细菌定植，例如肠道中的细菌。关于细菌的方式知之甚少 构成人类微生物组的意义或对RCS的反应，预计这种反应至关重要 为了使细菌与人类免疫系统相互作用。这项研究提出了 应用将使用转录组，遗传，生化和系统生物学技术来识别和 表征细菌用来感知和反应RC的基因，蛋白质和途径，并将使用 哺乳动物细胞培养和动物研究，以测试这些机制在宿主 - 微生物相互作用中的作用。 我们的短期至中期目标集中在肠道微生物大肠杆菌和乳酸杆菌氏菌。大肠杆菌是 在生理学上的特征很好，易于操纵和促炎，而L. reuteri是抗 炎症性并与健康的微生物组相关。我们将识别并表征RCS感应 这些生物体中的调节剂，并表征了这些调节剂和的分子机制 他们控制的基因可保护细菌免受RCS介导的损伤，并影响 细菌及其哺乳动物宿主。从长远来看，这些研究将扩展到其他模型 细菌以表征跨微生物组多样性的RCS响应。最终目标 这项研究是了解医学上重要细菌中的RCS压力反应，尤其是专注于 他们在定植和发病机理中扮演的角色。该研究计划的结果将推进 氧化应激反应领域，阐明RCS感应转录的体内特异性的基础 因素，有助于了解RCS毒性的根本原因，并可能导致对新颖的识别 细菌与先天免疫系统之间相互作用的机制。这可能会导致新 针对越来越多的炎症性疾病清单的微生物靶向治疗已知受到影响 微生物组，可能对我们对宿主微叶相互作用的理解具有广泛的影响， 多种生物的发病机理，定植和RCS耐受性。