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

基本信息

批准号：
10681234
负责人：
Ansel Hsiao
金额：
$ 78.75万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/10681234
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 Repression 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 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 virulence gene

项目摘要

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.

项目概要人类病原体霍乱弧菌是称为霍乱的严重腹泻病的病原体，每年影响全世界数百万人。为了使霍乱弧菌成功定植于宿主的小肠，它必须表达一系列毒力因子，这一直是研究的主要焦点霍乱研究。然而，细菌致病性是体内的一个多因素过程，不仅取决于毒力因子表达，但宿主对感染的反应以及与共生微生物的相互作用肠道，肠道微生物组。霍乱弧菌必须克服的一组主要宿主产生的因素包括一氧化氮 (NO) 和 NO 衍生的氮氧化物以及二亚硝基铁络合物，统称为作为亚硝化应激（活性氮物种，RNS）。先前的研究表明，诱导型一氧化氮合酶（iNOS 或 NOS2）是合成 NO 的酶，是体内调节最为上调的蛋白质之一。霍乱期间的十二指肠组织，我们的结果表明霍乱弧菌高度诱导 iNOS 成年小鼠模型感染，并且 iNOS-/- 小鼠或接受治疗的小鼠中霍乱弧菌定植减少与 iNOS 抑制剂氨基胍 (AG) 一起使用。然而，关于体内RNS如何增加却知之甚少。影响霍乱弧菌、肠道微生物组以及驱动最终结果的微生物间相互作用感染。我们假设感染期间诱导的 RNS 产生调节结构、功能和肠道微生物群的病原体相互作用，使霍乱弧菌比共生菌具有竞争优势由于几种 RNS 抗性机制与毒力因子表达一起受到严格调节。我们将从两个目标来检验这个假设。在目标 1 中，我们将阐明霍乱弧菌如何响应 RNS 感染期间，以及这些反应如何与毒力一起调节。在目标 2 中，我们将检查 RNS 在调节肠道微生物组中的作用，RNS 依赖性变化如何影响霍乱弧菌易感性，以及 RNS 如何影响该病原体与共生肠道之间的特定微生物相互作用微生物。