Role of the Thrombin PAR-1 Pathway in Viral Infection

这项提议的广泛、长期目标是了解组织因子-凝血酶-PAR-1的作用 病毒感染的途径。这是一个未被充分研究的领域。病毒感染可通过多种细胞内 受体，包括Toll样受体（TLR）3。凝血系统在病毒感染期间被激活， 宿主的先天免疫反应凝血系统中的凝血蛋白酶，如凝血酶， 细胞通过切割PAR，包括PAR-1。在人类中，PAR-1是血小板上的主要凝血酶受体， 是新型抗血小板药物伏拉帕沙的靶点。小鼠的血小板上不表达PAR-1， 研究PAR-1在血小板以外的细胞中的作用。我们发现组织因子-凝血酶-PAR-1 途径保护小鼠免受柯萨奇病毒B3（CVB 3）和甲型流感病毒（IAV）的感染。我们发现 PAR-1激活增强TLR 3依赖的IFNβ表达。I型干扰素反应在 在对抗病毒感染中的作用。目前的提议将扩展我们令人兴奋的发现，并确定 应用多种免疫组织化学方法检测柯萨奇病毒3型（CVB 3）诱导的心肌炎和IAV感染肺组织中不同细胞类型PAR-1的表达。 转基因小鼠品系我们的建议有两个具体目标。具体目标1：确定PAR-1的作用 在宿主对CVB 3诱导的心肌炎的反应中，不同类型的细胞表达。一般假设：PAR- 1通过增强IFNβ的表达和通过抑制IFNβ的表达来促进心脏对CVB 3感染的抗病毒反应， 抑制病毒复制。具体目标2：确定PAR-1在不同细胞类型中表达的作用， 宿主对甲型流感的反应。一般假设：EC的PAR-1表达有助于维持 血管完整性和造血细胞上的PAR-1调节IAV后肺中的抗病毒应答 感染病毒感染在世界范围内造成相当大的发病率和死亡率。我们的研究意义重大 因为它们可能阐明宿主防御系统中用于对抗病毒感染的新途径。

The broad, long-term objective of this proposal is to understand the role of the tissue factor-thrombin-PAR-1 pathway in viral infections. This is an understudied area. Viral infections are detected by various intracellular receptors, including toll-like receptor (TLR) 3. The clotting system is activated during viral infections as part of the host innate immune response. Coagulation proteases, such as thrombin, in the clotting system activated cells by cleavage of PARs, including PAR-1. In humans PAR-1 is the major thrombin receptor on platelets and is the target of the new antiplatelet drug vorapaxar. Mice do not express PAR-1 on their platelets and allow us to investigate the role of PAR-1 in cells other than platelets. We found that the tissue factor-thrombin-PAR-1 pathway protected mice from infection with coxsackievirus B3 (CVB3) and influenza A virus (IAV). We found that PAR-1 activation enhanced TLR3-dependent IFNβ expression. A type I interferon response plays a central role in fighting viral infections. The current proposal will extend our exciting discovery and determine the role of PAR-1 in different cell types in CVB3-induced myocarditis and IAV infection of the lung using a variety of transgenic mouse lines. Our proposal has 2 specific aims. Specific Aim 1: Determine the role of PAR-1 expressed on different cell types in the host response to CVB3-induced myocarditis. General hypothesis: PAR- 1 contributes to the antiviral response to CVB3 infection of the heart by enhancing IFNβ expression and by inhibiting viral replication. Specific Aim 2: Determine the role of PAR-1 expressed on different cell types in the host response to influenza A. General hypothesis: PAR-1 expression by EC contributes to the maintenance of vascular integrity and PAR-1 on hematopoietic cells regulates the antiviral response in the lung after IAV infection. Viral infections cause considerable morbidity and mortality worldwide. Our studies are significant because they may elucidate new pathways in the host defense system that are used to combat viral infections.