Role of the Thrombin PAR-1 Pathway in Viral Infection

凝血酶 PAR-1 途径在病毒感染中的作用

• 批准号: 9380482
• 负责人: Nigel Mackman
• 金额: $ 38.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9380482
• 关键词: Antiplatelet Drugs; Antiviral Response; Area; Blood Platelets; Blood Vessels; CXCL10 gene; Cardiac; Cardiac Myocytes; Cell model; Cells; Coagulation Process; Coxsackie Viruses; Double-Stranded RNA; Ebola virus; Endothelial Cells; Epithelial Cells; Exhibits; Fibroblasts; Goals; Grant; HIV; Heart; Hematopoietic; Hepatocyte; Host Defense; Human; Immune response; Infection; Influenza A virus; Innate Immune Response; Interferon Type I; Lung; Maintenance; Morbidity - disease rate; Mus; Mutate; Myocarditis; PAR-1 Receptor; Pathology; Pathway interactions; Peptide Hydrolases; Play; Poly I-C; RNA Viruses; Role; Series; System; TLR3 gene; Thrombin; Thrombin Receptor; Thromboplastin; Toll-like receptors; Transgenic Mice; Viral Pneumonia; Virus; Virus Diseases; Virus Replication; activated Protein C; cell type; combat; fighting; macrophage; mimetics; mortality; mouse model; novel; pathogen; receptor; response

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.

这项提议的广泛、长期的目标是了解组织因子-凝血酶-PAR-1的作用 病毒感染的途径。这是一个研究不足的领域。病毒感染是通过各种细胞内的 受体，包括Toll样受体(TLR)3。凝血系统在病毒感染过程中被激活，作为 宿主的先天免疫反应。凝血系统中被激活的凝血酶，如凝血酶 细胞通过裂解PARs，包括PAR-1。在人类中，PAR-1是血小板上的主要凝血酶受体， 是抗血小板新药沃拉帕沙的靶点。小鼠的血小板上不表达PAR-1，因此我们可以 目的：探讨PAR-1在非血小板细胞中的作用。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(CVB3)和甲型流感病毒(IAV)的感染。我们发现 PAR-1激活增强了依赖TLR3的干扰素β的表达。I型干扰素反应起着中枢作用 在抗击病毒感染方面的作用。目前的提案将扩大我们令人兴奋的发现，并确定 不同细胞类型的PAR-1在CVB3诱导的心肌炎和IAV肺部感染中的作用 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CVB3诱导的心肌炎宿主反应中的不同细胞类型上的表达。一般假设：PAR- 1通过增强干扰素β的表达和通过以下途径参与抗病毒反应 抑制病毒复制。特定目标2：确定不同细胞类型表达的PAR-1在 宿主对甲型流感的反应一般假设：EC表达PAR-1有助于维持 血管完整性和造血细胞表面PAR-1调节IAV后肺内抗病毒反应 感染。病毒感染在全世界造成相当大的发病率和死亡率。我们的研究很有意义 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。