Evasion of Innate Immunity by Group A Streptococcus

A 组链球菌逃避先天免疫

• 批准号: 8417645
• 负责人: BENFANG LEI
• 金额: $ 33.51万
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417645
• 关键词: Acute Pharyngitis; Address; Animal Model; Antibiotics; C5a peptidase; CXC Chemokines; Chemotaxis; Clinical; 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 therapy; Production; Regulation; Relative (related person); Research; Role; Sepsis; Serotyping; Site; Skin; Soft Tissue Infections; Streptococcal Infections; Streptococcus pyogenes; Streptococcus vaccine; System; Testing; Time; Vaccines; Variant; Virulence; Virulence Factors; base; esterase; genome-wide; in vivo; lipid mediator; migration; mouse model; mutant; neutrophil; novel; novel strategies; pathogen; platelet activating factor receptor; prevent; response; streptolysin S; subcutaneous

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（申请人提供）：A族链球菌（GAS）是一种主要的人类病原体，可引起多种疾病，包括相对轻微的咽炎和皮肤感染以及严重的侵袭性感染，例如败血症和坏死性筋膜炎。不幸的是，目前还没有获得许可的 GAS 疫苗，并且严重的侵袭性感染很难用常规抗生素治疗。对 GAS 发病机制的基本了解对于制定预防和治疗该生物体引起的感染的新策略至关重要。该项目的目标是阐明 GAS 逃避先天免疫的机制。根据我们的初步研究，我们假设 GAS 分泌的酯酶（称为 SsE）在抑制 GAS 早期中性粒细胞募集方面发挥着关键作用，从而使 GAS 全身扩散，导致脓毒症等严重疾病。我们进一步假设 SsE 水解血小板激活因子并与其他因子协同作用以阻碍中性粒细胞反应。我们追求以下具体目标：（1）确定 SsE 是否是 GAS 抑制早期中性粒细胞募集所必需的； (2)确定SsE是否通过水解血小板活化因子介导抑制早期中性粒细胞浸润； nd (3) 测试链球菌溶血素 S 是否是高毒力血清型 M3 菌株的 sse 突变体皮下感染期间中性粒细胞反应晚期崩溃的原因。拟议的研究促进了两项进展。首先，它们将增加我们对 GAS 发病机制和侵袭性 GAS 感染进展的了解。其次，他们将确定开发广泛、有效的 GAS 疫苗和预防和治疗 GAS 感染的新疗法的目标。总体而言，该项目有可能定义一种通过 GAS 逃避先天免疫的新机制，并建立细菌抑制中性粒细胞募集和功能的范例。