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: 10330036
• 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/10330036
• 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; 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/文摘