Scl1-mediated immune evasion of the rheumatologenic group A Streptococcus

描述（由申请人提供）：A组链球菌（GAS）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避免宿主免疫系统杀死宿主并鉴定交叉反应性GAS抗原的机制对于成功对抗链球菌感染至关重要。因此，长期目标是确定链球菌胶原样蛋白1（Scl 1）是一种不可或缺的辅助蛋白，它有助于诱发风湿性M6型GAS的发病机制，从而诱导抗胶原自身免疫。本申请集中于Scl 1在免疫逃避中的作用，作为发病机制的初始步骤。本申请的目的是定义因子H与GAS细胞上天然Scl 1结合的机制，并确定Scl 1-因子H相互作用在人血液中GAS存活和小鼠发病机制中的重要性。我们提出两个具体目标：（1）表征天然Scl 1蛋白与正常和异常H因子的相互作用，并确定Scl 1蛋白结合H因子在GAS逃避补体介导的破坏中的作用;（2）证明小鼠感染期间Scl 1-H因子相互作用增强疾病进展。将使用遗传解剖、体外结合和功能测定以及使用正常和H因子耗竭小鼠的体内研究的组合来实现这些目标。我们假设Scl 1是主要的H因子结合分子，其对于在体外完全保护M6型GAS免受补体介导的调理作用和吞噬作用是必要的。此外，我们还提出，在体内Scl 1的H因子结合增强GAS生存和感染传播的小鼠。这项研究有望证明Scl 1是GAS免疫逃避的主要决定因素。与公共卫生的相关性：拟议的研究将填补我们对GAS免疫逃避机制的理解中的一个关键空白。针对这些机制可能是对抗GAS感染的有效策略。 公共卫生相关性：A组链球菌（GAS）感染是世界范围内重大人类发病率和死亡率的原因，但没有有效的全球干预战略。GAS细胞含有对发病重要的表面蛋白。我们研究的目的是描述细胞表面蛋白Scl 1在GAS免疫逃避中的作用。我们的研究将有助于了解这些细菌在人类免疫反应中存活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.