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

宿主止血系统在A族链球菌致病性中的作用

• 批准号: 7359339
• 负责人: Hongmin Sun
• 金额: $ 20.6万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7359339
• 关键词: Affect; Antibiotic Resistance; Antibiotic Therapy; Bacterial Infections; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Bypass; Communicable Diseases; Data; Depth; Drug usage; Engineering; Factor V; Fibrin; Fibrinogen; Fibrinolytic Agents; Generations; Genetic Variation; Glomerulonephritis; Heart Valve Diseases; Hemostatic Agents; Host Defense; Human; Infection; Knock-out; Knockout Mice; Modeling; Morbidity - disease rate; Mus; Pathogenesis; Pathogenicity; Patients; Penetration; Phagocytosis; Phase; Plasma; Plasminogen; Plasminogen Activator; Play; Predisposition; Relative (related person); Resistance; Rheumatic Fever; Role; Site-Directed Mutagenesis; Streptococcal Infections; Streptococcus; Streptococcus pyogenes; Streptokinase; System; Testing; Thrombin; Thrombosis; Tissues; Variant; Virulence; Virulence Factors; base; design; in vivo; inhibitor/antagonist; mouse genome; mouse model; multiple myeloma M Protein; mutant; novel; novel therapeutics; pathogen; therapeutic target

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.

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。除了直接感染发病外，许多患者还遭受感染后后遗症，包括风湿热，风湿热是全世界瓣膜性心脏病的主要原因。链激酶 (SK) 是一种主要的 GAS 毒力因子，链激酶/纤溶酶原相互作用已被确定为链球菌发病机制的关键因素。然而，SK在GAS感染中致病的确切机制仍不清楚。在该提议中，假设局部血栓形成在宿主抵御细菌感染的防御中发挥关键作用，并且GAS利用SK劫持宿主纤溶系统以绕过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会影响宿主对 GAS 感染的易感性。 本提案中概述的研究将研究 SK 在 GAS 致病性中的作用的各个方面。在具体目标 1 中，将测试新型 SK 抑制剂对 GAS 致病性的影响，并通过比较表达人纤溶酶原的小鼠中野生型和 SK 敲除 GAS 菌株的全身传播来研究 SK 在 GAS 侵袭性中的作用。 GAS 感染中 SK 的时间需求将被确定。此外，通过比较表达野生型 SK 的 GAS 与纤维蛋白依赖性突变体 SK60-414 的毒力，将探讨宿主纤溶酶原的纤维蛋白依赖性和纤维蛋白非依赖性 SK 激活在 GAS 致病性中的作用。在具体目标 2 中，将测试宿主止血因子（例如因子 V 和纤维蛋白原）的变化对宿主对 GAS 感染的易感性的影响。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 感染启动中的作用。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。上述研究收集的数据将进一步了解宿主止血系统对宿主细菌感染易感性的影响。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 (GAS) 是一种重要的人类病原体，可导致数百万例感染以及感染后疾病。在我们之前的研究中，宿主止血系统已被证明与GAS感染有关。该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。