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: 10418819
• 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/10418819
• 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; 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; antagonist; antimicrobial; arms race; colonization resistance; combat; commensal bacteria; commensal microbes; cytotoxicity; delivery vehicle; 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.

病原菌在宿主体内复杂和恶劣的环境中生存。几个主机-和 微生物群衍生的因子在感染期间抑制病原体生长。成功的病原体通过 利用其直接环境中的线索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组链球菌（GAS）是 在口咽感染期间与一种细菌进行军备竞赛。共生 细菌产生一种以前未知的抗菌代谢物， 有助于宿主防御人口咽中的GAS定植。作为对策，GAS 利用分泌的半胱氨酸蛋白酶SpeB，一种主要的毒力因子， 通过蛋白水解降解抗菌代谢物。尽管我们的实验证据 提示GAS与肠道细菌之间存在拮抗作用， 调节抗菌代谢产物的产生及其对SpeB产生的影响 气体未知。最近，我们发现了一种新的GAS群体感应途径， 一类新的细菌群体感应信号，一种无前导的分泌肽，和一种细胞内的 在感染过程中控制speB暂时表达的受体。有趣的是， 细菌还采用无前导肽依赖性群体感应途径来控制细菌的生长。 抗微生物代谢产物的产生。然而，我们的初步数据表明，气体劫持 唾液酸肽信号诱导其内源性群体感应途径并激活SpeB 生产这一发现与GAS发病机制高度相关，因为种间信号传导促进了GAS的发生。 在次优宿主环境中产生毒力因子并促进GAS毒力。使用 结合微生物、遗传学、生物化学和成像的多学科方法 方法，和动物感染研究，我们将解剖的分子细节内和间， 物种信号传导，表征两种细菌物种之间的拮抗机制， 确定其对GAS发病机制的影响，并阐明细胞间信号传导的机制， 无前导肽在四个特定的目标。这项研究的结果将阐明肽是如何 信号通路是为生产细菌的生理需要量身定制的， 病原体通过劫持来自微生物的非同源信号来获得生存优势， 引发毒力因子产生并导致疾病。这项研究具有重要意义，因为 研究了一种主要人类病原体的疾病发病机理的关键过程，并可能 阐明了对抗GAS感染的新的翻译策略。