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: 10619021
• 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/10619021
• 关键词: Anabolism; Animals; Anti-Bacterial Agents; Antibiotics; Bacteria; Bacterial Infections; Biochemical; Biological; 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; 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; human pathogen; in vivo; interdisciplinary approach; microbiota; mouse model; novel; novel therapeutic intervention; oral commensal; pathogen; pathogenic bacteria; peptide synthase; polyketides; prevent; programs; quorum sensing; receptor; resistance mechanism; scaffold; secondary metabolite; 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而恶劣的环境中生存。几个主机-和 微生物区系衍生的因子在感染期间抑制病原体的生长。成功的病原体通过 利用其邻近环境中的线索来协调毒力的时空产生 各种因素。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共生细菌进行军备竞赛。共生关系 细菌通过一种新的化学支架产生一种以前未知的抗微生物代谢物，这种化学支架可能 有助于宿主防御人类口咽部的气体定植。作为对策，天然气 利用分泌的半胱氨酸蛋白酶SpeB，一个主要的毒力因子，来克服共生防御 通过蛋白质降解抗菌代谢产物。尽管我们的实验证据 提示GAS和共生菌之间存在拮抗作用，其影响因素和机制 共生菌中抗菌代谢产物的调控及其对SpeB产生的影响 是由气体造成的，目前尚不清楚。最近，我们发现了一种新的气体群体感应通路，它由一个 一类新的细菌群体感应信号，一种无领导的分泌肽和一种细胞内 在感染过程中控制SpeB的瞬时表达的受体。有趣的是，这种共生关系 细菌还使用无领导的多肽依赖的群体感应途径来控制 抗菌代谢物生产。然而，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感应通路并激活SpeB 制作。这一发现与GAS的发病机制高度相关，因为物种间的信号传递促进了 毒力因子在次优寄主环境中产生，并促进气体毒力。使用 结合微生物学、遗传学、生化和成像的多学科方法 方法学和动物感染研究，我们将剖析内部和之间的分子细节。 物种信号，表征了两个细菌物种之间的拮抗机制， 确定其在GAS发病机制中的影响，并阐明细胞间信号转导的机制 四个特定目标中的无引导肽。这项研究的结果将阐明多肽是如何 信号通路是为产生细菌的生理需求而定制的，以及如何 病原菌通过劫持来自共生微生物的非同源信号来获得生存优势 触发毒力因子的产生并导致疾病。拟议的研究具有重要意义，因为它 研究人类主要病原体在疾病发病机制中的关键过程，并可能 阐明对抗气体感染的新的翻译策略。