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
Coagulation systems in invertebrates and vertebrates play a major role in the innate immune response to infection by limiting the spread of the pathogen. In addition, coagulation proteases can contribute to the innate immune system by cleaving PARs on host cells. New anti-thrombotic drugs that target thrombin and PAR-1 reduce thrombosis but may interfere with the protective roles of the TF-thrombin-PAR-1 pathway in viral infection.
|Owens 3rd, Albert Phillip; Byrnes, James Robert; Mackman, Nigel (2014) Hyperlipidemia, tissue factor, coagulation, and simvastatin. Trends Cardiovasc Med 24:95-8|
|Mackman, Nigel (2014) New targets for atherothrombosis. Arterioscler Thromb Vasc Biol 34:1607-8|
|Antoniak, Silvio; Mackman, Nigel (2014) Multiple roles of the coagulation protease cascade during virus infection. Blood 123:2605-13|
|Antoniak, Silvio; Mackman, Nigel (2014) Coagulation, protease-activated receptors, and viral myocarditis. J Cardiovasc Transl Res 7:203-11|
|Mackman, Nigel; Antoniak, Silvio (2014) Roles of PAR1 and PAR2 in viral myocarditis. Thromb Res 133 Suppl 1:S18-20|