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: 8706957
• 负责人: Nigel Mackman
• 金额: $ 37.24万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706957
• 关键词: Agonist; Bacteria; Binding; CXCL10 gene; Cardiac; Cardiac Myocytes; Cells; Cleaved cell; Coagulation Process; Coxsackie Viruses; Drug Targeting; Employee Strikes; Endothelial Cells; Epithelial Cells; Fibrin; Fibroblasts; Gene Expression; Generations; Genes; Genetic; Health; Herpesvirus 1; Host Defense; Immune response; Immune system; Individual; Infection; Inflammation; Influenza; Interferons; Invertebrates; Lead; Lung; MAPK14 gene; Morbidity - disease rate; Mus; Myocardial tissue; Myocarditis; PAR-1 Receptor; Pathway interactions; Peptide Hydrolases; Play; Poly I-C; Predisposition; Principal Investigator; Role; Signal Pathway; System; Thrombin; Thromboplastin; Thrombosis; Vertebrates; Viral; Virus; Virus Diseases; Wild Type Mouse; cell type; clinically significant; defense response; human TLR3 protein; inhibitor/antagonist; killings; macrophage; mortality; pathogen; programs

DESCRIPTION (provided by applicant): Viral infections cause considerable morbidity and mortality worldwide. Toll-like receptor 3 (TLR3) plays a major role in the innate immune response to viruses. The coagulation system is also activated by viral infections as part of the host defense response. Tissue factor (TF) and protease-activated receptor 1 (PAR-1) are induced in various cell types during viral infection. However, there are few studies on the roles of coagulation and PARs in viral infection. We observed that inhibition of TF or thrombin, as well as a deficiency of PAR-1 significantly increased coxsackievirus B3 (CVB3)-induced myocarditis. PAR-1 deficient mice were also more susceptible to infection with influenza A. Activation of TLR3 on cardiac fibroblasts (CFs), cardiac myocytes (CMs) and lung epithelial cells induces interferon ¿ (IFN-¿) expression and IFN-¿-regulated genes, such as CXCL10, as part of the immune response to viral infection. We found that PAR-1 deficient mice had reduced IFN-¿ and CXCL10 expression during viral infection. In addition, activation of PAR-1 on CFs enhanced IFN-¿ expression in a p38-dependent manner. Taken together, these results indicate that the TF-thrombin-PAR-1 pathway plays important roles in the early innate immune response to two different types of viral infections. We will use genetic and pharmacologic approaches to determine the roles of TF, thrombin and PAR-1 in viral infection. Our proposal consists of 3 specific aims. Specific Aim 1: Determine the roles of TF, thrombin and PAR-1 in CVB3-induced myocarditis. Hypothesis: Myocardial TF-dependent thrombin generation activates PAR-1 and increases the IFN- ¿-dependent anti-viral program after CVB3 infection. Specific Aim 2: Determine the mechanisms by which PAR-1 enhances TLR3-dependent IFN-¿ expression in CFs and CMs. Hypothesis: PAR-1 activation enhances TLR3-dependent IFN-¿ gene expression by increasing various intracellular signaling pathways. Specific Aim 3: Determine the roles of TF, thrombin and PAR-1 in influenza A infection of the lung. Hypothesis: TF-dependent thrombin generation and PAR-1 activation in the lung contributes to the innate immune response to influenza A infection. Our studies will elucidate how the coagulation system and PAR-1 contribute to the innate immune response to viral infection

描述（由申请人提供）：病毒感染在全世界引起相当大的发病率和死亡率。 Toll 样受体 3 (TLR3) 在针对病毒的先天免疫反应中发挥着重要作用。作为宿主防御反应的一部分，病毒感染也会激活凝血系统。病毒感染期间，各种细胞类型都会诱导组织因子 (TF) 和蛋白酶激活受体 1 (PAR-1)。然而，关于凝血和PARs在病毒感染中的作用的研究很少。我们观察到抑制 TF 或凝血酶以及 PAR-1 的缺乏会显着增加柯萨奇病毒 B3 (CVB3) 诱发的心肌炎。 PAR-1缺陷小鼠也更容易受到甲型流感病毒感染。心脏成纤维细胞（CF）、心肌细胞（CM）和肺上皮细胞上TLR3的激活会诱导干扰素¿（IFN-¿）表达和IFN-¿调节基因，例如CXCL10，作为病毒感染免疫反应的一部分。我们发现 PAR-1 缺陷小鼠在病毒感染期间 IFN-¿ 和 CXCL10 表达降低。此外，CFs上PAR-1的激活以p38依赖性方式增强了IFN-¿的表达。综上所述，这些结果表明 TF-凝血酶-PAR-1 途径在针对两种不同类型病毒感染的早期先天免疫反应中发挥着重要作用。我们将使用遗传和药理学方法来确定 TF、凝血酶和 PAR-1 在病毒感染中的作用。我们的提案包含 3 个具体目标。具体目标 1：确定 TF、凝血酶和 PAR-1 在 CVB3 诱导的心肌炎中的作用。假设：CVB3 感染后，心肌 TF 依赖性凝血酶生成激活 PAR-1 并增强 IFN-β 依赖性抗病毒程序。具体目标 2：确定 PAR-1 增强 CF 和 CM 中 TLR3 依赖性 IFN-¿ 表达的机制。假设：PAR-1 激活通过增加各种细胞内信号传导途径增强 TLR3 依赖性 IFN-¿ 基因表达。具体目标 3：确定 TF、凝血酶和 PAR-1 在甲型流感肺部感染中的作用。假设：肺中 TF 依赖性凝血酶生成和 PAR-1 激活有助于对甲型流感感染的先天免疫反应。我们的研究将阐明凝血系统和 PAR-1 如何促进针对病毒感染的先天免疫反应