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

描述(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外，许多患者还遭受感染后的后遗症，包括风湿热，这是全世界瓣膜心脏病的主要原因。链激酶(SK)是一种主要的GAS毒力因子，链酶/纤溶酶原相互作用是链球菌致病的关键因素。然而，SK在GAS感染中致病的确切机制仍不清楚。在这一建议中，假设局部血栓在宿主抵御细菌感染的防御中发挥关键作用，GAS利用SK劫持宿主纤溶系统，绕过宿主防御，促进细菌感染。该模型预测，止血因素之间的遗传变异可能会影响宿主对GAS感染的易感性。 这项提案中概述的研究将研究SK在气体致病中所起作用的各个方面。具体目标1，通过比较野生型和SK基因敲除的GAS菌株在表达人纤溶酶原的小鼠体内的全身传播，测试新型SK抑制剂对GAS致病性的影响，并研究SK在GAS侵袭性中的作用。将确定SK在气体感染中的时间需求。此外，还将通过比较表达GAS野生型SK和纤维蛋白依赖突变体SK60-414的毒力，探讨宿主纤溶酶原激活纤维蛋白依赖和非纤维蛋白依赖性SK在GAS致病中的作用。在特定的目标2中，将测试宿主止血因子的变化，如因子V和纤维蛋白原，对宿主对GAS感染的易感性的影响。将研究血浆和血小板Fv池对宿主防御的相对贡献。纤维蛋白原缺失的小鼠将被用来研究纤维蛋白原在启动GAS感染中的作用。此外，还将探讨纤维蛋白原和GAS M蛋白在GAS吞噬抵抗中的作用。以上研究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群链球菌(GAS)是一种重要的人类病原体，可导致数百万人感染和感染后的疾病。在我们以前的研究中，宿主止血系统已经被证明与气体感染有关。这项建议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.