Vibrio cholerae antinitrosative stress defenses and gut microbiome interaction

霍乱弧菌抗亚硝化应激防御和肠道微生物组相互作用

• 批准号: 10470881
• 负责人: Ansel Hsiao
• 金额: $ 78.45万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-23 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470881
• 关键词: Adult; Affect; Animals; Antibiotics; Cholera; Cholera Toxin; Communities; Complex; Cysteine; Developing Countries; Diarrhea; Disease Resistance; Duodenum; Enzymes; Escherichia coli; Etiology; Gene Expression; Genes; Genomic Islands; Germ-Free; Goals; Grant; Growth; Human; Human Microbiome; Immune response; In Vitro; Infection; Intervention; Island; Lactobacillus; Metagenomics; Microbe; Microbial Biofilms; Modeling; Molecular; Morbidity - disease rate; Mus; NOS2A gene; Nitric Oxide; Nitrogen Oxides; Outcome; Pathogenesis; Pathogenicity; Persons; Poison; Post-Translational Protein Processing; Predisposition; Process; Production; Protein S; Proteins; Proteomics; Reactive Nitrogen Species; Regulation; Research; Resistance; Risk Factors; Role; Series; Shapes; Site; Small Intestines; Stress; Structure; Tissues; Variant; Vibrio cholerae; Vibrio cholerae infection; Virulence; Virulence Factors; Wild Type Mouse; aminoguanidine; base; biological adaptation to stress; chemical property; commensal microbes; diarrheal disease; dinitrosyl iron complex; gastrointestinal function; gut microbes; gut microbiome; gut microbiota; human pathogen; in vivo; inhibitor; member; microbiome; microorganism interaction; mortality; mouse model; nitrosative stress; novel; pathogen; prophylactic; protective effect; resistance mechanism; response; transposon sequencing

PROJECT SUMMARY The human pathogen Vibrio cholerae is the etiologic agent of the severe diarrheal disease known as cholera, which affects millions of people annually, worldwide. In order for V. cholerae to successfully colonize in the small intestines of the host, it must express a series of virulence factors, which have been the main focus of the cholera research. However, bacterial pathogenicity is a multifactorial process in vivo that depends not only on virulence factor expression, but host responses to infection and interactions with the commensal microbes of the gut, the gut microbiome. One major set of host-produced factors that must be overcome by V. cholerae comprises nitric oxide (NO) and NO-derived nitrogen oxides and dinitrosyl-iron complexes, collectively known as nitrosative stress (reactive nitrogen species, RNS). Previous studies show that inducible nitric oxide synthase (iNOS or NOS2), the enzyme that synthesizes NO, is among the most upregulated proteins in duodenal tissue during cholera, and our results show both that iNOS is highly induced upon V. cholerae infection of an adult mouse model, and that V. cholerae colonization is reduced in iNOS-/- mice or mice treated with the iNOS inhibitor aminoguanidine (AG). However, little is known about how increased RNS in vivo impacts V. cholerae, the gut microbiome, and the inter-microbial interactions that drive the ultimate outcome of infection. We hypothesize that RNS production induced during infection modulates the structure, function, and pathogen interactions of the gut microbiome, granting V. cholerae a competitive advantage over commensals due to several RNS-resistance mechanisms that are tightly regulated alongside virulence factor expression. We will examine this hypothesis in two aims. In Aim 1, we will elucidate how V. cholerae responds to RNS during infection, and how these responses are regulated alongside virulence. In Aim 2, we will examine the role of RNS in modulating the gut microbiome, how RNS-dependent changes influences V. cholerae susceptibility, and how RNS affects specific microbial interactions between this pathogen and commensal gut microbes.

项目总结 人类病原体霍乱弧菌是一种被称为霍乱的严重腹泻疾病的病原体， 每年影响全球数百万人。为了使霍乱弧菌在 在寄主小肠中，它必须表达一系列毒力因子，而这些毒力因子一直是主要关注的焦点 霍乱研究。然而，细菌的致病性在体内是一个多因素的过程，不仅取决于 毒力因子的表达，但宿主对感染的反应以及与共生微生物的相互作用 肠道的微生物群。霍乱弧菌必须克服的一组主要宿主产生的因素 由一氧化氮(NO)和NO衍生的氮氧化物和二亚硝基铁络合物组成，统称为 作为亚硝化胁迫(反应氮物种，RNS)。先前的研究表明，诱导性一氧化氮 合成酶(iNOS或NOS2)是合成NO的酶，是体内最上调的蛋白质之一 霍乱期间的十二指肠组织，我们的结果表明iNOS对霍乱弧菌有很高的诱导作用 成年小鼠模型的感染，以及在iNOS-/-小鼠或经治疗的小鼠中霍乱弧菌定植减少 使用诱导型一氧化氮合酶抑制剂氨基胍(AG)。然而，关于活体内RNS增加的原因还知之甚少 影响霍乱弧菌、肠道微生物群以及推动霍乱最终结果的微生物之间的相互作用 感染。我们假设在感染过程中诱导产生的RNS调节结构、功能和 肠道微生物群的病原体相互作用，使霍乱弧菌具有相对于共生菌的竞争优势 由于RNS的几种抗性机制与毒力因子的表达密切相关。 我们将从两个方面检验这一假说。在目标1中，我们将阐明霍乱弧菌对RNS的反应 在感染过程中，以及这些反应如何与毒力一起调节。在目标2中，我们将研究 RNS在调节肠道微生物群中的作用，RNS依赖的变化如何影响霍乱弧菌 敏感性，以及RNS如何影响病原体和共生肠道之间的特定微生物相互作用 微生物。