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

British Journal of Pharmacology
Vuong Ba LêGuy Boivin

Abstract

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. Pharmacological approaches were used to investigate the role of PAR1 during RSV and hMPV infection, in vitro using epithelial A549 cells and in vivo using a mouse model of virus infection. In vitro, the PAR1 antagonist RWJ-56110 reduced the replication of RSV and hMPV in A549 cells. In agreement with these results, RWJ-56110-treated mice were protected against RSV and hMPV infections, as indicated by less weight loss and mortality. This protective effect in 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 effec...Continue Reading

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Citations

Aug 14, 2018·The Journal of General Virology·Ba Vuong LêGuy Boivin
Dec 26, 2018·Arteriosclerosis, Thrombosis, and Vascular Biology·Jens J PosmaNigel Mackman
Sep 2, 2020·Cardiovascular Drugs and Therapy·Kholoud F Aliter, Rami A Al-Horani
Jul 9, 2020·British Journal of Pharmacology·Krishna Sriram, Paul A Insel
Apr 4, 2021·Viruses·Nicolás M S GálvezAlexis M Kalergis

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