INTERACTION OF GROUP A STREP WITH THE PLASMINOGEN SYSTEM

性状（改编自申请人摘要）：A组链球菌 是与多种疾病相关的重要人类病原体 包括咽炎、脓疱病和侵袭性感染，如蜂窝织炎 和菌血症。 近年来，链球菌感染的发病率和严重程度 疾病增加了，侵袭性表型的确切性质没有 被充分阐明。 波义耳博士实验室的研究表明，A组链球菌可以 与人纤溶酶（原）系统相互作用的许多不同的 获得表面蛋白水解酶活性的机制， 被生理蛋白酶抑制剂如α-2抗纤溶酶抑制。 这些途径包括纤溶酶直接结合到表面结合 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，表明获得这种宿主蛋白酶活性 增强A组链球菌引起全身感染的能力。 A群链球菌与人相互作用的意义 纤溶酶（原）系统将通过以下步骤进行研究：1）建立宿主， 获得表面纤溶酶原激活物所需的细菌因子， 纤溶酶（原）依赖性酶活性的条件下， 在受感染的宿主中;和2）确定获得性感染的后果。 在皮肤感染的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，使用远系繁殖的CD 1小鼠作为 以及在重组的转基因纤溶酶原基因敲除小鼠中的研究 与小鼠或人纤溶酶原。 关键细菌因子的调控 参与获得宿主纤溶酶（原）依赖性活性， 模拟A组链球菌可能遇到的条件 受感染的主机也将被分析。 这些研究将有助于更清楚地了解 A组链球菌与人纤溶酶（原）系统的重要性 这种相互作用的过程中，严重程度，和性质的侵入性 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， 对致病过程的理解是重要的。

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.