Proteolytic regulation of the Streptococcus pyogenes cell surface

化脓性链球菌细胞表面的蛋白水解调节

• 批准号: 10209054
• 负责人: Christopher N LaRock
• 金额: $ 38.3万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209054
• 关键词: Acute; Acute Pharyngitis; Address; Agonist; Antibiotics; Antimicrobial Resistance; Automobile Driving; Bacteremia; Bacteria; Binding; Biochemical; Cell Surface Proteins; Cell Wall; Cell surface; Cessation of life; Childhood; Cleaved cell; Data; Detection; Development; Disease; Environment; Event; Feedback; Gene Expression Regulation; Genetic; Glomerulonephritis; Goals; Homeostasis; Host Defense; Human; Immune; Immune System Diseases; Impetigo; Individual; Infection; Inflammation; Inflammatory; Integration Host Factors; Interleukin-1 beta; Lead; Link; Mediating; Microbe; Mission; Modeling; Molecular; Morbidity - disease rate; National Institute of Allergy and Infectious Disease; Necrotizing fasciitis; Pathogenesis; Pathologic; Pathology; Peptide Hydrolases; Peptides; Pharyngeal structure; Pharyngitis; Population; Prevention; Process; Production; Proteins; Proteolysis; Public Health; Regulation of Proteolysis; Repression; Research; Resistance; Rheumatic Fever; Rheumatic Heart Disease; Role; Scarlet Fever; Signal Transduction; Site; Streptococcus; Streptococcus pyogenes; Sum; Surface; System; Therapeutic; Time; Toxic Shock Syndrome; Vaccines; Virulence; Virulence Factors; biochemical tools; capsule; cytokine; human pathogen; in vivo; innovation; insight; mortality; multiple myeloma M Protein; mutant; neutrophil; novel; novel therapeutic intervention; pathogen; prevent; prophylactic; protein function; response; therapeutic target; therapeutically effective; tool

PROJECT SUMMARY/ABSTRACT Streptococcus pyogenes (Spy; group A Streptococcus) is the most prolific pathogen in the number of distinct diseases it is responsible for. Most commonly Spy is a cause of childhood acute pharyngitis (strep throat), but it is also a top-10-pathogen in mortality that results in more than half a million deaths annually through invasive infections and immune diseases that include necrotizing fasciitis, toxic shock syndrome, and acute rheumatic fever. Despite their public health importance, the pathogenesis of these severe diseases is poorly understood, and they remain challenging to treat. Our long-term goal seeks to determine how Spy virulence factors contribute to the development of these more severe forms of disease so that effective therapeutic countermeasures can be developed. Our previous studies show that the streptococcal protease SpeB acts directly on the host cytokine pro-IL-1β to induce inflammatory pathology during invasive infection. We hypothesize that additional proteins targeted by SpeB, from both host and microbe, contribute to the proinflammatory responses we see during infection. In our preliminary data, we have characterized the biochemical activity of SpeB and identified two of its substrates that cooperatively lead to fundamental shifts in pathogenesis. In our first aim, we examine how SpeB regulates the activities of M protein, a pleiotropic virulence factor with numerous host targets. By eliminating domains specific for the binding of some host molecules or anchoring of M protein to the Spy surface, SpeB directly contributes to pathological complications of infection like glomerulonephritis and toxic shock syndrome. In our second aim, we define the molecular determinates of how SpeB blocks signaling by the CovR/CovS two-component regulator by targeting its agonist, the host defense peptide LL-37. This mechanism results in a positive-feedback loop for SpeB production and repression of capsule and other cell surface factors that alter antimicrobial resistance, detection by the host, and promotes inflammation and disease complications. Both aims take advantage of new genetic and biochemical tools we developed for targeted control and specific detection of SpeB and its substrates. These innovations allow us for the first time to separate activities for these multifunctional proteins and examine in vivo dramatic switch in the virulence strategy of Spy regulated by SpeB. The expected contribution of the proposed research is an expanded understanding of how Spy pathogenesis is regulated that provides attractive therapeutic targets for the prevention and treatment of severe Spy disease and insights into orthologous systems of other pathogens highly relevant to the NIAID mission.

项目总结/摘要 化脓性链球菌（Streptococcus pyogenes）（Spy; A组链球菌）是在不同的细菌数量方面最多的病原体。 疾病负责。最常见的间谍是一个原因，儿童急性咽炎（链球菌咽喉），但它 也是死亡率最高的10种病原体，每年通过侵入性感染导致50多万人死亡。 感染和免疫性疾病，包括坏死性筋膜炎、中毒性休克综合征和急性风湿性关节炎。 发烧尽管这些严重疾病对公共卫生具有重要意义，但人们对它们的发病机制知之甚少， 我们的长期目标是确定Spy毒力因子是如何起作用的， 这些更严重形式的疾病的发展，以便有效的治疗对策， 发展。我们以前的研究表明，链球菌蛋白酶SpeB直接作用于宿主细胞因子 pro-IL-1β在侵袭性感染过程中诱导炎症病理。我们假设额外的蛋白质 宿主和微生物的SpeB靶向，有助于我们在治疗过程中看到的促炎反应。 感染在我们的初步数据中，我们已经表征了SpeB的生化活性，并确定了两种 其底物协同导致发病机制的根本转变。在我们的第一个目标中，我们研究如何 SpeB调节M蛋白的活性，M蛋白是一种具有许多宿主靶标的多效性毒力因子。通过 消除了对某些宿主分子的结合或M蛋白锚定到Spy表面的特异性结构域， SpeB直接导致感染的病理并发症，如肾小球肾炎和中毒性休克 综合征在我们的第二个目标中，我们定义了SpeB如何阻断信号传导的分子决定因素， CovR/CovS双组分调节剂通过靶向其激动剂，宿主防御肽LL-37。这一机制 导致SpeB产生的正反馈回路以及对荚膜和其他细胞表面因子的抑制 改变抗菌素耐药性，被宿主检测到，并促进炎症和疾病并发症。 这两个目标都利用了我们开发的新的遗传和生化工具，用于靶向控制和特异性免疫。 SpeB及其底物的检测。这些创新使我们能够首次将这些活动分开， 多功能蛋白质和检查在体内的Spy的毒力策略的SpeB调节的戏剧性开关。 这项研究的预期贡献是扩大了对Spy发病机制的理解， 调节，为预防和治疗严重Spy疾病提供有吸引力的治疗靶点， 深入了解与NIAID使命高度相关的其他病原体的正向系统。