Coagulation, protease-activated receptors, and viral myocarditis

Abstract

The coagulation protease cascade plays an essential role in hemostasis. In addition, a clot contributes to host defense by limiting the spread of pathogens. Coagulation proteases induce intracellular signaling by cleavage of cell surface receptors called protease-activated receptors (PARs). These receptors allow cells to sense changes in the extracellular environment, such as infection. Viruses activate the coagulation cascade by inducing tissue factor expression and by disrupting the endothelium. Virus infection of the heart can cause myocarditis, cardiac remodeling, and heart failure. A recent study using a mouse model have shown that tissue factor, thrombin, and PAR-1 signaling all positively regulate the innate immune during viral myocarditis. In contrast, PAR-2 signaling was found to inhibit interferon-β expression and the innate immune response. These observations suggest that anticoagulants may impair the innate immune response to viral infection and that inhibition of PAR-2 may be a new strategy to reduce viral myocarditis.

Figure. The thrombin PAR-1 pathway enhances TLR3-depdendent innate immune responses in CVB3 myocarditis

CVB3 infection leads to increased TF expression and activation of coagulation. Thrombin mediated PAR-1 cleavage contribute to TLR3 dependent IFN-β due to increase in p38 activation on cardiac cells, such as cardiac fibroblasts. Additionally, PAR-1 can be activated by MMP13 and enhances TLR3 signaling during viral infection.