The roles of host hemostatic system in the pathogenicity of Group A Streptococcal

描述（由申请人提供）：A组链球菌（GAS）是一种重要的人类病原体，每年影响全球数百万人。除了直接的感染性发病率，许多患者还遭受感染后后遗症，包括风湿热，这是全世界心脏瓣膜病的主要原因。链激酶（SK）是GAS的主要毒力因子，链激酶/纤溶酶原相互作用已被确定为链球菌致病的关键因素。然而，SK在GAS感染中致病性的确切机制仍不清楚。在该提议中，假设局部血栓形成在宿主防御细菌感染中起关键作用，并且GAS利用SK劫持宿主纤溶系统以绕过该宿主防御并促进细菌感染。该模型预测止血因子之间的遗传变异可能影响宿主对GAS感染的易感性。 本提案中概述的研究将研究SK在GAS致病性中作用的各个方面。在具体目标1中，将测试新型SK抑制剂对GAS致病性的影响，并通过比较野生型和SK敲除GAS菌株在表达人纤溶酶原的小鼠中的全身传播来研究SK在GAS侵袭性中的作用。将确定SK在GAS感染中的时间要求。此外，将通过比较表达野生型SK的GAS与纤维蛋白依赖性突变体SK 60 - 414的毒力，探索宿主纤溶酶原的纤维蛋白依赖性和非纤维蛋白依赖性SK激活在GAS致病性中的作用。在特定目标2中，将检测宿主止血因子（如因子V和纤维蛋白原）的变化对宿主对GAS感染易感性的影响。将研究血浆和血小板FV库对宿主防御的相对贡献。纤维蛋白原缺失小鼠将用于研究纤维蛋白原在GAS感染起始中的作用。纤维蛋白原和GAS M蛋白在GAS吞噬抵抗中的作用也将被研究。从上述研究中收集的数据将进一步加深我们对宿主止血系统对宿主对细菌感染易感性的贡献的理解。因此，除了抗生素治疗之外，还可以探索通过干扰宿主止血系统与细菌的相互作用来治疗细菌感染的替代方法。 A族链球菌（Group A Streptococcus，GAS）是一种重要的人类病原体，引起数百万例感染以及感染后疾病。在我们以前的研究中，宿主止血系统已被证明参与GAS感染。本提案的总体目标是了解宿主止血系统如何与GAS相互作用，并确定治疗GAS感染的新治疗靶点。

DESCRIPTION (provided by applicant): Group A Streptococcus (GAS) is an important human pathogen affecting millions people globally each year. In addition to the direct infectious morbidity, numerous patients also suffer post-infectious sequelae including rheumatic fever, a major cause of valvular heart disease throughout the world. Streptokinase (SK) is a major GAS virulence factor and the streptokinase/plasminogen interaction has been established as a critical factor in streptococcal pathogenesis. However, the precise mechanism underlying the pathogenicity of SK in GAS infection is still unclear. In this proposal, it is hypothesized that local thrombosis plays a critical role in host defense against bacterial infection and that GAS utilizes SK to hijack the host fibrinolytic system to bypass this host defense and facilitate bacterial infection. This model predicts that genetic variations among hemostatic factors might affect host susceptibility to GAS infection. The studies outlined in this proposal will study various aspects of SK's roles in GAS pathogenicity. In Specific Aim 1 the impact of novel SK inhibitors on GAS pathogenicity will be tested and the role of SK in GAS invasiveness will be studied by comparing the systemic spread of wild type and SK knockout GAS strains in mice expressing human plasminogen. The temporal requirement of SK in GAS infection will be determined. In addition, the roles of fibrin-dependent and fibrin-independent SK activation of host plasminogen in GAS pathogenicity will be explored by comparing the virulence of GAS expressing wild type SK versus SK60-414, a fibrin-dependent mutant. In Specific Aim 2 the effects of variations in host hemostatic factors, such as Factor V and fibrinogen, on host susceptibility to GAS infection will be tested. The relative contributions of plasma and platelet FV pools to host defense will be studied. Fibrinogen null mice will be used to study the role of fibrinogen in initiation of GAS infection. The role of fibrinogen and GAS M protein in GAS phagocytosis resistance will be also investigated. Data collected from the above studies will further our understanding of the contribution of host hemostatic system to host susceptibility to bacterial infection. As a result, alternative approach to treat bacterial infection by interfering with host hemostatic system's interaction with bacterial can be explored in addition to antibiotic treatment. Group A Streptococcus (GAS) is an important human pathogen that causes millions cases of infection as well as post infectious diseases. Host hemostatic system has been shown to be involved in GAS infection in our previous studies. The overall objective of this proposal is to understand how the host hemostatic system interacts with GAS and to identify novel therapeutic targets for treatment of GAS infections.