INTERACTION OF GROUP A STREP WITH THE PLASMINOGEN SYSTEM

描述(改编自申请人的摘要)：A组链球菌 是与多种疾病相关的重要的人类病原体 包括咽炎、脓疱病和蜂窝织炎等侵袭性感染 和菌血症。近年来，链球菌的发病率和严重程度 疾病增加了，而侵袭性表型的确切性质并没有 得到了充分的阐明。 博伊尔博士实验室的研究表明，A组链球菌可以 与人类纤溶酶(原)系统通过多种不同方式相互作用 获得表面蛋白水解酶活性的机制，这不能 被α-2抗纤溶酶等生理性蛋白酶抑制剂抑制。 这些途径包括纤溶酶与表面结合的直接结合 蛋白质，以及涉及两种宿主蛋白质的更复杂的途径 (纤溶酶原和纤维蛋白原)和两种细菌蛋白(分泌的 细菌纤溶酶原激活剂、链激酶(SK)和一种表面 纤维蛋白原结合蛋白)。初步证据，使用小鼠模型 皮肤感染，表明获得了这种宿主的蛋白酶活性 增强A组链球菌引起全身感染的能力。 A组链球菌与人类相互作用的意义 纤溶酶(原)系统的研究将通过：1)建立宿主和 获得表面纤溶酶原激活剂所需的细菌因子和 在可能存在的条件下纤溶酶(原)依赖的酶活性 在感染的宿主中；以及2)确定获得性 皮肤感染小鼠模型中的酶活性。这些研究将 使用已建立的皮肤感染小鼠模型，使用杂交种CD1小鼠作为 以及重组转基因纤溶酶原基因敲除小鼠的研究 用小鼠或人的纤溶酶原。关键细菌因子的调控 参与获得宿主纤溶酶(原)依赖的活性 模拟A组链球菌可能在 还将分析受感染的主机。 这些研究将使我们更清楚地了解 A组链球菌与人纤溶酶(原)系统的关系及其重要性 这种相互作用对侵袭性疾病的过程、严重性和性质的影响 感染。随着报告的死亡率和发病率的增加 与侵袭性链球菌感染相关的更全面的 对致病过程的了解很重要。

DESCRIPTION (Adapted from the applicant's abstract): Group A streptococci are significant human pathogens associated with a variety of diseases including pharyngitis, impetigo, and invasive infections such as cellulitis and bacteremia. Recently, the incidence and severity of streptococcal disease has increased and the exact nature of the invasive phenotype has not been fully elucidated. Studies in Dr. Boyle's laboratory have shown that group A streptococci can interact with the human plasmin(ogen) system by a number of different mechanisms to acquire surface proteolytic enzymatic activity, which cannot be inhibited by physiological protease inhibitors like alpha-2 antiplasmin. These pathways include direct binding of plasmin to surface binding proteins, as well as a more complicated pathway involving two host proteins (plasminogen and fibrinogen) and two bacterial proteins (the secreted bacterial plasminogen activator, streptokinase (SK), and a surface fibrinogen-binding protein). Preliminary evidence, using a mouse model of skin infection, suggests that acquisition of this host protease activity enhances the ability of group A streptococci to cause a systemic infection. The significance of the interaction of group A streptococci with the human plasmin(ogen) system will be studied by: 1) establishing the host and bacterial factors required for acquiring surface plasminogen activator and plasmin(ogen)-dependent enzymatic activity under conditions that would exist in the infected host; and 2) determining the consequences of the acquired enzymatic activity in a mouse model of skin infection. These studies will use an established mouse model of skin infection using outbred CD1 mice as well as studies in transgenic plasminogen gene knock-out mice reconstituted with mouse or human plasminogen. Regulation of key bacterial factors involved in acquisition of host plasmin(ogen)-dependent activity under conditions that mimic those group A streptococci could encounter in the infected host will also be analyzed. These studies will lead to a clearer understanding of the interaction of group A streptococci with the human plasmin(ogen) system and the importance of this interaction on the course, severity, and nature of invasive infections. With the reported increase in mortality and morbidity associated with invasive streptococcal infections, a more comprehensive understanding of the pathogenic process is important.