Mechanisms of the M protein in group A Streptococcus virulence

A组链球菌M蛋白的毒力机制

• 批准号: 8675796
• 负责人: PARTHO GHOSH
• 金额: $ 52.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675796
• 关键词: Acute; Address; Adopted; Animal Model; Antibody Activation; Autoimmune Process; Bacteria; Binding; Binding Sites; Biochemical; Biochemistry; Biological Assay; Clinical; Collaborations; Complement; Complementarity Determining Regions; Complex; Deposition; Disease; Failure; Fibrinogen; Goals; Human; Immune system; In Vitro; Indium; Infection; Infectious Skin Diseases; Integration Host Factors; Joints; Knowledge; Laboratories; Lead; Life; Manuscripts; Mentorship; Molecular Conformation; Molecular Genetics; Mutagenesis; Natural Immunity; Neutrophil Activation; Patients; Peptide Hydrolases; Pharyngeal structure; Physiological; Population; Prevention strategy; Procedures; Process; Property; Protein Binding; Protein Fragment; Proteins; Recruitment Activity; Research Personnel; Resistance; Rheumatic Fever; Role; Sepsis; Sequence Homology; Site; Sorting - Cell Movement; Specificity; Streptococcal Infections; Streptococcus; Streptococcus pyogenes; Structure; Surface; Symptoms; Systemic infection; Toxic Shock Syndrome; Variant; Vasodilator Agents; Virulence; Virulence Factors; Work; base; cationic antimicrobial protein CAP 37; complement 4b-binding protein; design; experience; gain of function; in vivo; killings; loss of function; mortality; mouse model; multiple myeloma M Protein; mutant; neutrophil; novel; novel therapeutics; pathogen; protein complex; research study; structural biology

DESCRIPTION (provided by applicant): Group A Streptococcus (GAS, S. pyogenes), which is responsible for ~500 million cases of strep throat annually, is also capable of causing severe invasive diseases (10,000 US cases annually) with high mortality rates (>30%), such as streptococcal toxic shock syndrome (STSS). Untreated GAS infection can also lead to serious autoimmune sequelae, including acute rheumatic fever. The M protein, the major surface-associated virulence factor of GAS, has a significant role in each of these disease processes. The M protein impairs phagocytic clearance of GAS by recruiting specific host factors to the GAS surface, the most common being fibrinogen (Fg) and C4b-binding protein (C4BP), that interfere with the deposition of opsonic antibodies and the activation of complement. Furthermore, the M1 type of M protein, after proteolytic release from the GAS surface, forms a proinflammatory complex with fibrinogen that contributes to STSS. Capitalizing on our recent structural discoveries on the M1 protein and its interactions with Fg, the goals of the project are to define the rules governing the interactions of various M protein types with Fg and with C4BP. In vitro and in vivo experiments will be carried out to determine how the M1 protein forms a pathogenic complex with Fg (Aim 1); whether other M types form pathogenic complexes with Fg, and if they do so, how this occurs (Aim 2); and how a remarkably broad variety of M protein types recruit C4BP to the GAS surface for protection through a region that is non-conserved and lacks apparent sequence homology (Aim 3). Once completed, these studies will provide essential knowledge applicable to the design of novel therapeutics or preventive strategies against GAS. This multi-PI proposal draws on the distinct yet highly complementary sorts of expertise in the Ghosh and Nizet laboratories. The Ghosh laboratory has extensive experience with the biochemistry and structural biology of bacterial virulence factors, and the Nizet laboratory has extensive experience in the molecular genetics of group A Streptococcus (GAS) and the study of GAS interactions with host innate immunity in vitro and in vivo. This five-year project will extend a successful approach of joint mentorship and collaboration that has yielded two manuscripts describing the crystal structures of M1 protein and the M1 protein-fibrinogen complex, and another joint manuscript detailing novel mechanisms by which M1 protein promotes GAS resistance to host neutrophil killing. Dr. Ghosh will directly supervise three postdoctoral researchers focusing on biochemical and structural approaches, and Dr. Nizet will directly supervise one postdoctoral researcher focusing on microbiological and immunological approaches.

描述（由申请人提供）：A组链球菌（Gas，S。pyogenes）每年约有5亿例链球菌性喉咙喉咙，也能够引起严重的侵入性疾病（每年10,000例美国病例），其死亡率很高（ > 30％），例如链球菌毒性休克综合征（STSS）。未处理的气体感染也会导致严重的自身免疫后遗症，包括急性风湿热。 M蛋白是气体的主要表面相关毒力因子，在这些疾病过程中的每一个中都起着重要作用。 M蛋白通过将特定的宿主因子募集到气体表面上会损害气体的吞噬清除率，最常见的是纤维蛋白原（FG）和C4B结合蛋白（C4BP），从而干扰了Opsonic抗体的沉积以及补体的活化。此外，从气体表面蛋白水解释放后的M1类型的M蛋白质形成了促纤维蛋白原的促炎络合物，从而有助于STSS。利用我们最近在M1蛋白上的结构发现及其与FG的相互作用，该项目的目标是定义管理各种M蛋白质与FG和C4BP相互作用的规则。将进行体外和体内实验，以确定M1蛋白如何形成与FG的致病复合物（AIM 1）；其他M类型是否与FG形成致病性复合物，如果它们这样做，则如何发生（AIM 2）；以及多种M蛋白质类型的广泛种类繁多，将C4BP募集到气体表面，以通过未经保存的区域保护并且缺乏明显的序列同源性（AIM 3）。完成后，这些研究将提供适用于新型治疗剂或预防性策略的基本知识。该多PI提案借鉴了Ghosh和Nizet实验室中独特但高度互补的专业知识。 GHOSH实验室在细菌毒力因子的生物化学和结构生物学方面具有丰富的经验，而Nizet实验室在A组链球菌（GAS）的分子遗传学方面具有丰富的经验，以及与宿主与宿主与宿主免疫相互作用的研究。这个为期五年的项目将延长一种成功的指导和协作方法，该方法产生了两种手稿，描述了M1蛋白和M1蛋白 - 纤维蛋白原复合物的晶体结构，以及另一种关节手稿，详细介绍了M1蛋白可以促进气体抵抗力的新型机制宿主中性粒细胞杀死。 Ghosh博士将直接监督着专注于生化和结构方法的三位博士后研究人员，Nizet博士将直接监督一名专注于微生物和免疫学方法的博士后研究人员。