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Molecular Mechanism of Virulence Regulation in Streptococcus Pyogenes

化脓性链球菌毒力调控的分子机制

基本信息

批准号：
10275779
负责人：
Muthiah Kumaraswami
金额：
$ 56.37万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-07 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10275779
关键词：
Anabolism Animals Anti-Bacterial Agents Antibiotics Bacteria Bacterial Infections Biochemical Caspase Cell physiology Cessation of life Chemicals Communication Communities Complex Conflict (Psychology)Cues Cytosol Data Development Disease Engineered Probiotics Environment Funding Future Gene Cluster Genetic Growth Health Host Defense Human Image Immune system In Vitro Infection Invaded Investigation Knowledge Left Mediating Membrane Methodology Microbiology Mission Molecular Oral cavity Oropharyngeal Pathogenesis Pathogenicity Pathway interactions Peptide Hydrolases Peptide Signal Sequences Peptides Pharyngeal structure Physiological Population Population Density Process Production Property Race Regulation Research Saliva Signal Pathway Signal Transduction Site Streptococcal Infections Streptococcus Streptococcus pyogenes Streptococcus salivarius United States National Institutes of Health Vesicle Virulence Virulence Factors antimicrobial arm colonization resistance combat commensal bacteria commensal microbes cytotoxicity disorder control extracellular host microbiota human pathogen in vivo interdisciplinary approach microbiota mouse model novel novel therapeutic intervention oral commensal pathogen pathogenic bacteria peptide synthase prevent programs quorum sensing receptor resistance mechanism scaffold spatiotemporal translational approach

项目摘要

Pathogenic bacteria survive in complex and hostile environments in the host. Several host- and microbiota-derived factors curb pathogen growth during infection. Successful pathogens respond by exploiting the cues in their immediate environment to coordinate spatiotemporal production of virulence factors. Our preliminary data indicate that the human pathogen group A streptococcus (GAS) is engaged in arms race with a commensal bacterium during oropharyngeal infection. The commensal bacteria produce a previously unknown antimicrobial metabolite with a novel chemical scaffold that may contribute to host defense against GAS colonization in human oropharynx. As a countermeasure, GAS employs secreted cysteine protease SpeB, a major virulence factor, to overcome commensal defenses by proteolytically degrading the antimicrobial metabolites. Despite our experimental evidence suggesting antagonism between GAS and commensal bacterium, the factors and mechanisms that regulate antimicrobial metabolite production in the commensal and their influence on SpeB production by GAS are unknown. Recently, we discovered a novel GAS quorum sensing pathway comprised of a new class of bacterial quorum sensing signal, a leaderless secreted peptide, and an intracellular receptor that controls the temporal expression of speB during infection. Interestingly, the commensal bacterium also employs a leaderless peptide-dependent quorum sensing pathway to control the antimicrobial metabolite production. However, our preliminary data suggest that GAS hijacks the commensal peptide signal to induce its endogenous quorum sensing pathway and activate SpeB production. This finding is highly relevant to GAS pathogenesis as the interspecies signaling facilitates virulence factor production in a suboptimal host environment and promotes GAS virulence. Using a multidisciplinary approach combining microbiological, genetic, biochemical and imaging methodologies, and animal infection studies, we will dissect the molecular details of intra- and inter- species signaling, characterize the mechanism of antagonism between the two bacterial species, determine its impact on GAS pathogenesis, and elucidate the mechanism of intercellular signaling by leaderless peptides in four specific aims. The results from this study will elucidate how the peptide signaling pathways are tailored for the physiological needs of the producing bacteria and how a pathogen gain survival advantage by hijacking the non-cognate signal from a commensal microbe to trigger virulence factor production and cause disease. The proposed research is significant as it investigates a critical process in disease pathogenesis of a major human pathogen and is likely to elucidate novel translational strategies to combat GAS infections.

致病菌在宿主体内复杂而恶劣的环境中存活。几个主持人和