Abstract 18765: PAR-1 Contributes to the Innate Immune Response to Viral Infection
Objective: Viral infections activate the blood coagulation cascade as part of the host defense response. Coagulation proteases, such as thrombin, induce cellular responses by cleaving protease-activated receptors (PARs). It has been proposed that infections are detected by a dual-sensor system consisting of PARs and Toll-like receptors (TLRs). In this study, we analyzed the role of PAR-1 in host defense against infection with coxsackievirus B3 (CVB3) and influenza A virus.
Methods: Wild-type (WT) and PAR-1 deficient (PAR-1-/-) mice were infected with either CVB3 or influenza A (H1N1/PR8). The innate immune response, viral load and inflammation were was analyzed. Bone-marrow transplantation experiments were performed to identify the cellular source of PAR-1 contributing to the innate immune response to CVB3. In addition, we analyzed the effect of PAR-1 activation on TLR3-dependent induction of interferon-β and CXCL10 expression in culture cardiac fibroblasts.
Results: PAR-1-/- mice exhibited a reduced innate immune response to both viral infections that led to higher viral titers and inflammation compared to WT mice. PAR-1-/- mice also exhibited increased CVB3-induced myocarditis. Bone marrow transplantation experiments demonstrated that PAR-1 on non-hematopoietic cells played a role in CVB3 infection, and mice overexpressing PAR-1 on cardiomyocytes had reduced myocarditis. Stimulation of PAR-1 on mouse cardiac fibroblasts enhanced p38 activation and TLR3-dependent induction of interferon-β and CXCL10.
Conclusion: Our results indicate that activation of PAR-1 contributes in a p38-dependent manner to the innate immune response to viral infection. The use of PAR-1 inhibitors to reduce platelet activation in patients with cardiovascular disease may increase their susceptibility to virus infections.
- © 2012 by American Heart Association, Inc.