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Mechanisms of Microbial Competition During Salmonella Infection

沙门氏菌感染期间微生物竞争的机制

基本信息

批准号：
10600681
负责人：
Lauren Christine Radlinski
金额：
$ 6.95万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10600681
关键词：
Acids Amino Acids Animal Model Antibiotic Resistance Antibiotic Therapy Antibiotics Attenuated Biochemical Reaction Buffers Carboxy-Lyases Catabolism Cataloging Cell Death Communities Consumption Cytoplasm Cytosol Dietary Fiber Discipline Disease Ecosystem Engineering Enterobacteriaceae Environment Family Fermentation Glean Gnotobiotic Goals Growth Homeostasis Host Defense Hypoxia Immunocompromised Host In Vitro Individual Infection Inflammation Inflammatory Response Intestines Invaded Knowledge Large Intestine Link Mediating Metabolic Pathway Microbe Modeling Modification Mus Nutrient Nutritional Outcome Pathway interactions Patients Play Predisposition Production Protons Public Health Reaction Research Resistance Role Salmonella Salmonella enterica Salmonella infections Salmonella typhimurium Secure Supplementation Testing Toxic effect Treatment Failure Type III Secretion System Pathway Virulence Virulence Factors Volatile Fatty Acids Work acid stress antimicrobial bacterial genetics biological adaptation to stress colonization resistance commensal microbes dysbiosis enteric infection enteric pathogen gastrointestinal gastrointestinal infection gut colonization gut homeostasis high risk improved in vivo innovation intestinal epithelium metabolomics microbial microbial community microbiome microbiota microorganism mouse model novel therapeutic intervention pH Homeostasis pathogen prevent programs

项目摘要

PROJECT SUMMARY The microbiota is a critical frontline barrier that protects the host from invading microorganisms and keeps resident opportunists in check. Frank pathogens such as Salmonella enterica serovar Typhimurium (STm), however, are adept at overcoming microbiota-mediated colonization resistance to cause dysbiosis and disease. Under homeostasis, antimicrobial short-chain fatty acids (SCFAs) produced by the microbiota protect the host by restricting pathogen replication through cytosol acidification. During infection, STm uses its type III secretion systems (T3SS) to trigger an inflammatory response that depletes SCFA-producing commensals. Current paradigm holds that the depletion of SCFA-producing species is a pre-requisite for luminal STm expansion. However, using an antibiotic-naïve mouse model we have observed that STm blooms 1000-fold 3-4 days prior to the onset of overt inflammation when SCFAs are abundant and the community composition of the microbiota is undisturbed. This implies that STm employs an as-of-yet undescribed strategy to restore pH homeostasis and grow in the presence of SCFAs during gastrointestinal colonization. Our preliminary findings suggest that proton- consuming metabolic pathways, including the amino acid decarboxylases CadA and SpeF, alleviate SCFA growth inhibition in vitro and are required for full virulence in vivo, yet it is unclear whether these pathways specifically mediate growth in the presence of SCFAs within the host, or how STm secures the metabolites that fuel these pathways in the nutrient-restricted gastrointestinal environment. I hypothesize that during colonization of the gastrointestinal tract, STm uses its T3SS to obtain host-derived amino acids that fuel proton-consuming reactions and restore pH homeostasis in the presence of commensal-produced SCFAs. The objective of this application is to elucidate how STm adapts to the intestinal environment and to use this understanding to develop my own independent research program that investigates how enteric pathogens overcome intrinsic protective barriers so that we may uncover new therapeutic approaches for bolstering colonization resistance in high-risk patients. In AIM1 we will assess the contribution of proton-consuming metabolic pathways in restoring pH homeostasis and growth in the presence of SCFAs in vitro, and investigate the role these pathways play in mediating early ecosystem invasion in vivo using conventional and gnotobiotic animal models. In AIM2 we will use bacterial genetics, murine infection models, and metabolomics to determine how STm uses its virulence factors to engineer a new gastrointestinal niche that supports dysbiotic Enterobacteriaceae expansion under homeostatic conditions. This mechanistic approach to microbiota research will provide causal links between pathogen-mediated environmental remodeling and changes in microbial growth conditions that cannot be gleaned from solely cataloging bacterial species. Successful completion of this work will reveal opportunities to enhance innate host defenses by identifying and targeting the metabolic pathways enteric pathogens use to overcome colonization resistance.

项目总结