3 years ago

Protease-activated receptor 1 inhibition protects mice against thrombin-dependent respiratory syncytial virus and human metapneumovirus infections

Guy Boivin, Béatrice Riteau, Chantal Rhéaume, Martine Jandrot-Perrus, Christian Couture, Marie-Christine Alessi, Vuong Ba Lê, Marie-Ève Hamelin
Background and Purpose Protease-activated receptor 1 (PAR1) has been demonstrated to be involved in the pathogenesis of viral diseases. However, its role remains controversial. The goal of our study was to investigate the contribution of PAR1 to respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) infections. Experimental approach Pharmacological approaches were used to investigate the role of PAR1 during RSV and hMPV, in vitro using epithelial A549 cells and in vivo using a mouse model of virus infections. Key Results In vitro, A549 cell treatment with the PAR1 antagonist RWJ-56110 reduced replication of RSV and hMPV. In agreement with these results, RWJ-56110-treated mice were protected against RSV and hMPV infections, as indicated by less weight loss and mortality. Protection of the mice correlated with decreased lung viral replication and inflammation. In contrast, hMPV-infected mice treated with the PAR1 agonist TFLLR-NH2 showed increased mortality, as compared to infected mice, which were left untreated. Thrombin generation was shown to occur downstream of PAR1 activation in infected mice via tissue factor exposure as part of the inflammatory response and thrombin inhibition by argatroban reduced the pathogenicity of the infection with no additive effect to PAR1 inhibition. Conclusion and Implications These data show that PAR1 plays a detrimental role during RSV and hMPV infections in mice via, at least, a thrombin-dependent mechanism. Thus, the use of PAR1 antagonists and thrombin inhibitors may be potential novel approaches for the treatment of RSV and hMPV infections.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bph.14084

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