Molecular Mechanism of Virulence Regulation in Streptococcus Pyogenes

化脓性链球菌毒力调控的分子机制

• 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
• 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

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.

致病细菌在宿主的复杂和敌对环境中生存。几个主机和 微生物群衍生的因素在感染过程中遏制病原体的生长。成功的病原体回应 利用其直接环境中的提示来协调毒力的时空产生 因素。我们的初步数据表明，人类病原体A链球菌（气）为 在口咽感染期间，与共生细菌进行武器竞赛。共生 细菌产生一种以前未知的抗菌代谢物，具有新型的化学支架，可能 有助于宿主防御人类口咽中的气体定植。作为对策，汽油 采用分泌的半胱氨酸蛋白酶SPEB（一种主要的毒力因子）来克服共生防御 通过蛋白水解降解抗菌代谢产物。尽管我们的实验证据 提示气体和共生细菌之间的拮抗作用，这些因素和机制 调节共生中的抗菌代谢产物及其对SPEB生产的影响 气体是未知的。最近，我们发现了一个新型的气体法定人数传感途径，该途径由 新的细菌群体传感信号，无领导者分泌的肽和细胞内 控制感染过程中SPEB的时间表达的受体。有趣的是，共同体 细菌还采用无领导肽依赖性的群体传感途径来控制 抗菌代谢产物产生。但是，我们的初步数据表明气体劫持了 共生肽信号诱导其内源性群体传感途径并激活SPEB 生产。随着种间信号传导的促进，这一发现与气体发病机理高度相关 次优的宿主环境中的毒力因子产生并促进气体毒力。使用 多学科方法结合了微生物，遗传，生化和成像 方法论和动物感染研究，我们将剖析内部和间间的分子细节 物种信号传导，表征两个细菌物种之间拮抗的机制， 确定其对气体发病机理的影响，并通过 无领导肽在四个特定目标中。这项研究的结果将阐明肽如何 信号通路是针对生产细菌的生理需求而定制的 病原体通过从共同微生物劫持非认知信号来获得生存优势 触发毒力因子产生并引起疾病。拟议的研究很重要 研究主要人类病原体的疾病发病机理的关键过程，很可能 阐明新型的翻译策略来打击气体感染。