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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：
10269020
负责人：
Ansel Hsiao
金额：
$ 79.08万
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/10269020
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 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/antagonist member microbiome microorganism interaction mortality mouse model nitrosative stress novel pathogen prophylactic protective effect resistance mechanism response transposon sequencing

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.

项目总结