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Characterization of a novel family of Small Regulatory Proteins modulating virulence in Enterobacteriaceae

调节肠杆菌毒力的新型小调节蛋白家族的表征

基本信息

批准号：
10560645
负责人：
Araceli ELVIRA Santiago
金额：
$ 41.12万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2022-02-02 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560645
关键词：
Acute Affect Animal Disease Models Attenuated Bacteria Bacterial Genome Binding Biochemical Biological Assay Cells Centers for Disease Control and Prevention (U.S.)ChIP-seq Childhood Citrobacter Citrobacter rodentium Clinical Coupled DNA Binding DNA-Protein Interaction Data Developing Countries Disease Enterobacteriaceae Epidemiology Exhibits Family Fluorescence Microscopy Gastroenteritis Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Goals Gram-Negative Bacteria Histones Homologous Gene Hospitalization Host Defense Human Impairment In Vitro Infection Infection prevention Intestines Kidney Knowledge Lifting Maps Meningitis Metabolism Microscopy Modeling Molecular Morbidity - disease rate Pathogenesis Phenotype Play Protein Family Proteins Public Health Regulation Regulator Genes Regulon Repression Role Salmonella Shigella Structure Surface Plasmon Resonance System Therapeutic Intervention Toxin Type III Secretion System Pathway Urinary tract infection Vaccines Vibrio Virulence Virulence Factors Yersinia biological adaptation to stress clinically relevant diarrheal disease enteric infection enteric pathogen enteroaggregative Escherichia coli enteropathogenic Escherichia coli fitness gene repression genetic regulatory protein genome-wide gut colonization gut inflammation human stem cells in vivo insight member mortality murine colitis mutant novel novel therapeutics novel vaccines pathogen pathogenic Escherichia coli pathogenic bacteria protein protein interaction prototype stem cell technology stem cells trait transcriptome vaccine strategy virulence gene

项目摘要

PROJECT SUMMARY/ABSTRACT In the United States, the Center for Disease Control and Prevention (CDC) has estimated that more than 200 million episodes of acute gastroenteritis occur annually, resulting in nearly 1 million hospitalizations and over 5000 deceases. Vaccines against enteric pathogens are not available due, in part, to limited knowledge of the many virulence mechanisms that enteropathogens have evolved to colonize, multiply and escape host defenses. We have recently discovered the ANR (AraC Negative Regulators) family, comprising a large number of small regulatory proteins produced by diverse clinically important enteric pathogens including Vibrio spp., Salmonella spp., Shigella spp., Yersinia spp., Citrobacter spp., enterotoxigenic (ETEC), enteropathogenic EPEC, enterohaemorragic (EHEC) and enteroaggregative E. coli (EAEC). Members of the ANR family modulate the expression of virulence factors such as fimbriae, toxins, type-3 and type-6 secretion systems, and genes associated with metabolism, stress-response and fitness, by protein-protein interactions with positive transcriptional regulators of the AraC/XylS family and negative regulators of the HNS family. Furthermore, the absence of this regulatory system affects bacterial pathogenesis in a natural model of infection. Our overall hypothesis is that the ANR family plays a critical role in the concerted regulation of fitness and virulence in pathogens of the Enterobacteriaceae family by taking concomitant control of AraC and HNS global regulators. Here, we propose to obtain mechanistic insights into ANR molecular interactions (AIM-1), regulation (AIM 2) and pathogenesis (AIM-3) using EAEC, EPEC and C. rodentium as pathogen models, human stem cell technology and a natural animal model of disease, coupled with genetic, biochemical and molecular approaches such as Surface Plasmon Resonance (SPR), Time-lapse fluorescence microscopy (TLFM) and ChIP-seq. Our proposed studies will advance our knowledge of global gene regulatory mechanisms that govern fitness and virulence in pathogenic bacteria, and will likely open new avenues for therapeutic intervention.

项目总结/文摘