Scl1-mediated immune evasion of the rheumatologenic group A Streptococcus

描述(由申请人提供)：A组链球菌(GAS)可引起良性至危及生命的感染，也可引发自身免疫性疾病，包括急性风湿热。详细了解GAS避免被宿主免疫系统杀死以定植宿主的机制，并识别交叉反应的GAS抗原对于成功抗击链球菌感染至关重要。因此，长期的目标是确定链球菌胶原样蛋白1(SCL1)是一种不可或缺的辅助蛋白，它在风湿性M6型GAS的发病机制中起重要作用，从而诱导抗胶原自身免疫。这一应用主要集中在Scl1在免疫逃避中的作用，作为发病机制的第一步。本应用的目的是确定因子H与GAS细胞上天然的Scl1结合的机制，并确定Scl1与因子H相互作用在人类血液中的GAS存活以及在小鼠发病中的重要性。我们提出了两个特定的目标：(1)表征天然的Scl1蛋白与正常和异常的H因子的相互作用，并确定Scl1蛋白与H因子结合在气体逃逸补体介导的破坏中的作用；(2)证明在小鼠感染过程中Scl1与H因子的相互作用促进了疾病的进展。为了实现这些目标，将结合遗传解剖、体外结合和功能分析，以及使用正常和因子H耗尽的小鼠进行的体内研究。我们推测，Scl1是主要的H结合分子，在体外完全保护M6型GAS免受补体介导的调理和吞噬作用。此外，我们还提出，在体内，因子H与Scl1结合可增强小鼠的GAS存活和感染传播。这项拟议的研究有望证明scl1是GAS免疫逃避的主要决定因素。与公共卫生的相关性：拟议的调查将填补我们对气体免疫逃避机制的理解的一个关键空白。以这些机制为目标可能是对抗气体感染的有效策略。 与公共卫生的相关性：A组链球菌(GAS)感染在世界范围内造成了重大的人类发病率和死亡率，但没有有效的全球干预战略。GAS细胞含有对发病机制很重要的表面蛋白。我们研究的目的是确定一种名为Scl1的细胞表面蛋白在气体免疫逃避中的作用。我们的研究将有助于理解这些细菌在人类免疫反应中幸存下来并产生疾病的一些机制。

DESCRIPTION (provided by applicant): Group A Streptococcus (GAS) causes benign to life-threatening infections that can also trigger autoimmune diseases, including acute rheumatic fever. A detailed understanding of the mechanisms by which GAS avoids killing by the host immune system to colonize the host and identifying cross-reactive GAS antigens is critical for a successful combating of streptococcal infections. Thus, the long-term objective is to determine that the streptococcal collagen-like protein 1 (Scl1) is an indispensable accessory protein, which is instrumental to the pathogenesis of rheumatogenic M6-type GAS that leads to induction of anti-collagen autoimmunity. This application is focused on the role of Scl1 in immune evasion as an initial step in pathogenesis. The objectives of this application are to define the mechanism of factor H binding to native Scl1 on GAS cells, and to determine the importance of Scl1-factor H interaction in GAS survival in human blood, and in the pathogenesis in mice. We propose two specific aims: (1) To characterize the interactions of native Scl1 protein with normal and abnormal factor H, and to define the role of factor H binding by the Scl1 protein in GAS escape from complement-mediated destruction; and (2) To demonstrate that Scl1-factor H interaction during mouse infection augments disease progression. A combination of genetic dissection, in vitro binding and functional assays, and in vivo studies using normal and factor H-depleted mice will be used to accomplish these goals. We hypothesize that Scl1 is the major factor H-binding molecule that is necessary for the full protection of the M6-type GAS from complement-mediated opsonization and phagocytosis in vitro. In addition, we also propose that factor H binding by Scl1 in vivo enhances GAS survival and infection dissemination in mice. The proposed study is expected to demonstrate that Scl1 is major determinant of GAS immune evasion. Relevance to public health: The proposed investigations will fill a critical gap in our understanding of the mechanisms of GAS immune evasion. Targeting these mechanisms could be an effective strategy against GAS infections. PUBLIC HEALTH RELEVANCE: Group A streptococcal (GAS) infections are responsible for significant human morbidity and mortality worldwide but there are no effective strategies for global intervention. GAS cells contain surface proteins that are important for pathogenesis. The objective of our research is to characterize the role of a cell surface protein, called Scl1, in GAS immune evasion. Our studies will contribute towards understanding some of the mechanisms by which these bacteria survive human immune responses and produce disease.