Abstract

Human metapneumovirus (hMPV) infection causes acute respiratory tract infections (RTI) which can result in hospitalization of both children and adults. To date, no antiviral or vaccine is available for this common viral infection. Immunomodulators could represent an interesting strategy for the treatment of severe viral infection. Recently, the role of protease-activated receptors (PAR) in inflammation, coagulation and infection processes has been of growing interest. Herein, the effects of a PAR1 agonist and a PAR1 antagonist on hMPV infection were investigated in BALB/c mice. Intranasal administration of the PAR1 agonist resulted in increased weight loss and mortality of infected mice. Conversely, the PAR1 antagonist was beneficial to hMPV infection by decreasing weight loss and clinical signs and by significantly reducing pulmonary inflammation, pro-inflammatory cytokine levels (including IL-6, KC and MCP-1) and recruitment of immune cells to the lungs. In addition, a significant reduction in pulmonary viral titers was also observed in the lungs of PAR1 antagonist-treated mice. Despite no apparent direct effect on virus replication during in vitro experiments, an important role for PAR1 in the regulation of furin expression in the lungs was shown for the first time. Further experiments indicated that the hMPV fusion protein can be cleaved by furin thus suggesting that PAR1 could have an effect on viral infectivity in addition to its immunomodulatory properties. Thus, inhibition of PAR1 by selected antagonists could represent an interesting strategy for decreasing the severity of paramyxovirus infections.

Highlights

  • Human metapneumovirus is a paramyxovirus responsible for acute respiratory tract infections that are especially severe in young children [1,2], elderly people [3,4] and immunocompromized individuals [5,6]

  • We showed that PAR1 activation increases weight loss and mortality in a mouse model of Human metapneumovirus (hMPV) infection

  • HMPV infection causes a wide spectrum of diseases from mild upper respiratory tract infections (RTI) to severe lower RTI such as bronchiolitis or pneumonia and can result in hospitalization of both children and adults [49]

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Summary

Introduction

Human metapneumovirus (hMPV) is a paramyxovirus responsible for acute respiratory tract infections that are especially severe in young children [1,2], elderly people [3,4] and immunocompromized individuals [5,6]. A nucleoside analogue licensed for treatment of severe human respiratory syncytial virus (hRSV) infections, exhibits moderate in vitro activity against hMPV and was found to be beneficial in the mouse model [18,19]. This antiviral has been used to treat a few severe cases of hMPV pneumonia in immunocompromised individuals [20,21,22]. The development of new antivirals and/or immunomodulatory strategies is warranted for the treatment of severe hMPV infections

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