PAR-1 contributes to the innate immune response during viral infection

Abstract

Coagulation is a host defense system that limits the spread of pathogens. Coagulation proteases, such as thrombin, also activate cells by cleaving PARs. In this study, we analyzed the role of PAR-1 in coxsackievirus B3-induced (CVB3-induced) myocarditis and influenza A infection. CVB3-infected Par1 -/-mice expressed reduced levels of IFN-β and CXCL10 during the early phase of infection compared with Par1 +/+ mice that resulted in higher viral loads and cardiac injury at day 8 after infection. Inhibition of either tissue factor or thrombin in WT mice also significantly increased CVB3 levels in the heart and cardiac injury compared with controls. BM transplantation experiments demonstrated that PAR-1 in nonhematopoietic cells protected mice from CVB3 infection. Transgenic mice overexpressing PAR-1 in cardiomyocytes had reduced CVB3-induced myocarditis. We found that cooperative signaling between PAR-1 and TLR3 in mouse cardiac fibroblasts enhanced activation of p38 and induction of IFN-β and CXCL10 expression. Par1 -/-mice also had decreased CXCL10 expression and increased viral levels in the lung after influenza A infection compared with Par1 +/+ mice. Our results indicate that the tissue factor/thrombin/PAR-1 pathway enhances IFN-β expression and contributes to the innate immune response during single-stranded RNA viral infection.

Multiple roles of the coagulation protease cascade during virus infection

“…15 PAR1ko mice expressed lower levels of IFN-b and CXCL10 after infection and had higher levels of CVB3 in their hearts compared with WT mice. 15 The reduced IFN-b expression was associated with reduced NK cell infiltration into the heart in PAR1ko mice compared with WT controls. 15 In addition, we found that thrombin stimulation of WT murine splenocytes, but not PAR1ko cells, increased NK cell activity.…”

“…27,28 HSV may activate the clotting system to coat virally infected cells with fibrin to reduce their recognition and killing by NK cells and phagocytes. 15,29 Interestingly, Sutherland and colleagues found that activation of PAR1 and PAR2 increases HSV infection of endothelial cells in vitro (Figure 1). 26,30 Recently, this group analyzed the role of TF in HSV1 infection in mice.…”

“…38 However, the more likely scenario during invasion of a pathogen is that TLRs are the major receptors that respond to infection and that PARs act by modulating TLR signaling. 15,39-42…”

“…Interestingly, we discovered that PAR1 activation enhanced TLR3-dependent expression of IFN-b and CXCL10 expression (Figure 4). 15 This enhancement was abolished in PAR1 knockout (ko) cells and appears to be mediated, in part, by a PAR1-dependent increase in the activation of p38. 15 We also observed a PAR1-dependent enhancement of poly I:C induction of IFN-b and CXCL10 expression in murine bone marrow-derived macrophages.…”

“…15 This enhancement was abolished in PAR1 knockout (ko) cells and appears to be mediated, in part, by a PAR1-dependent increase in the activation of p38. 15 We also observed a PAR1-dependent enhancement of poly I:C induction of IFN-b and CXCL10 expression in murine bone marrow-derived macrophages. 46 Recently, we found that activation of PAR1 inhibited poly I:C induction of TNF-a expression by CFs and inhibited LPS induction of TNF-a expression by mouse embryonic fibroblasts (Michael F. J.…”