Evasion of Innate Immunity by Group A Streptococcus

描述(申请人提供)：A组链球菌(GAS)是一种主要的人类病原体，可导致多种疾病，包括相对轻微的咽炎和皮肤感染，以及严重的侵袭性感染，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，严重的侵袭性感染很难用传统的抗生素治疗。对GAS发病机制的基本了解对于开发预防和治疗由这种微生物引起的感染的新策略至关重要。本项目的目标是阐明GAS逃避天然免疫的机制。根据我们的初步研究，我们假设GAS的分泌酯酶(简称SSE)在抑制GAS早期的中性粒细胞募集中发挥关键作用，从而允许GAS的全身扩散导致严重的疾病，如败血症。我们进一步假设SSE能水解血小板激活因子，并与其他因子(S)协同作用以抑制中性粒细胞的反应。我们追求以下特定目标：(1)确定SSE是否是抑制GAS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激活因子介导抑制早期中性粒细胞的渗透；(3)检测链溶菌素S是否对超强毒力M3毒株的SSE突变株皮下感染过程中中性粒细胞反应的后期崩溃负责。拟议的研究促进了两个进展。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，作为结果，他们将确定开发广泛、有效的气体疫苗和预防和治疗气体感染的新疗法的目标。总体而言，该项目有可能定义一种新的GAS逃避天然免疫的机制，并建立一种细菌抑制中性粒细胞招募和功能的范例。

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.