Evasion of Innate Immunity by Group A Streptococcus

A 组链球菌逃避先天免疫

• 批准号: 9001240
• 负责人: BENFANG LEI
• 金额: $ 35.65万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-03 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9001240
• 关键词: Acute Pharyngitis; Address; Animal Model; Antibiotics; CXC Chemokines; Chemotaxis; Clinical; Complement 5a; Data; Development; Disease; Genes; Genetic; Goals; Human; Hydrolysis; IL8 gene; Immune; Immune response; Immune system; In Vitro; Infection; Infectious Skin Diseases; Inflammation; Interleukin-8; Investigation; Licensing; Mediating; Medical; Molecular; Mus; Mutation; Natural Immunity; Necrotizing fasciitis; Neutrophil Activation; Neutrophil Infiltration; Organism; Pathogenesis; Patients; Pattern; Peptide Hydrolases; Pharyngitis; Platelet Activating Factor; Play; Prevention; Production; Regulation; Research; Role; Sepsis; Serotyping; Site; Skin; Soft Tissue Infections; Streptococcal Infections; Streptococcus pyogenes; Streptococcus vaccine; Streptolysins; System; Testing; Time; Vaccine Therapy; Vaccines; Variant; Virulence; Virulence Factors; base; esterase; genome-wide; in vivo; lipid mediator; migration; mouse model; mutant; neutrophil; novel; novel strategies; novel therapeutics; pathogen; platelet activating factor receptor; prevent; response; subcutaneous; treatment group

DESCRIPTION (provided by applicant): Group A Streptococcus (GAS) is a major human pathogen that causes a variety of diseases, including relatively mild pharyngitis and skin infection and severe invasive infections such as sepsis and necrotizing fasciitis. Unfortunately, there is no licensed GAS vaccine, and severe invasive infections are difficult to treat with conventional antibiotics. A fundamental understanding of GAS pathogenesis is essential to the development of novel strategies to prevent and treat infections caused by this organism. The goal of this project is to clarify the mechanism for evasion of innate immunity by GAS. Based upon our preliminary studies, we hypothesize that the secreted esterase of GAS (designated SsE) plays a critical role in the inhibition of early neutrophil recruitment by GAS, which then allows the systemic spread of GAS to cause severe disease like sepsis. We further hypothesize that SsE hydrolyzes the platelet-activating factor and acts in tandem with other factor(s) to impede neutrophil responses. We pursue the following specific aims: (1) Determine whether SsE is required for inhibition of early neutrophil recruitment by GAS; (2) Determine whether SsE mediates inhibition of early neutrophil infiltration via hydrolysis of platelet-activating factor; nd (3) Test whether streptolysin S is responsible for the late collapse of neutrophil responses during subcutaneous infection of a sse mutant of a hypervirulent serotype M3 strain. The proposed studies promote two advancements. First, they will increase our understanding of GAS pathogenesis and progression of invasive GAS infections. Second, as a result, they will identify targets for development of a broad, efficacious GAS vaccine and new therapies for prevention and treatment of GAS infections. Overall, this project has the potential to define a novel mechanism for evasion of innate immunity by GAS and to establish a paradigm for bacterial inhibition of neutrophil recruitment and function.

描述（由申请人提供）：A组链球菌（气）是一种主要的人类病原体，可引起各种疾病，包括相对温和的咽炎和皮肤感染以及严重的浸润性感染，例如败血症和坏死性筋膜炎。不幸的是，没有许可的气体疫苗，严重的侵入性感染很难用常规抗生素治疗。对气体发病机理的基本了解对于制定预防和治疗该生物引起的感染的新型策略至关重要。该项目的目的是阐明气体逃避先天免疫的机制。基于我们的初步研究，我们假设天然气（指定的SSE）分泌的酯酶在抑制气体早期嗜中性粒细胞募集中起着至关重要的作用，然后允许气体的全身传播引起类似败血症的严重疾病。我们进一步假设，SSE水解血小板激活因子，并与其他因子同时起作用以阻碍中性粒细胞反应。我们追求以下特定目的：（1）确定是否需要SSE抑制气体早期嗜中性粒细胞募集； （2）确定SSE是否通过血小板激活因子的水解介导了早期嗜中性粒细胞浸润的抑制作用； nd（3）测试链霉素是否是导致嗜中性粒细胞反应的晚期塌陷，在皮下感染过度毒性血清型M3菌株的SSE突变体的皮下感染期间。拟议的研究促进了两个进步。首先，它们将增加我们对侵入性气体感染的气体发病机理和进展的理解。其次，因此，他们将确定开发广泛，有效的天然气疫苗和新疗法的靶标，以预防和治疗气体感染。总体而言，该项目有可能定义一种新的通过气体逃避先天免疫的机制，并建立一个范式抑制中性粒细胞募集和功能的范式。