Human metapneumovirus (hMPV) infection causes acute respiratory tract infections (RTI) which can result inhospitalization 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, therole of protease-activated receptors (PAR) in inflammation, coagulation and infection processes has been of growinginterest. Herein, the effects of a PAR1 agonist and a PAR1 antagonist on hMPV infection were investigated inBALB/c mice. Intranasal administration of the PAR1 agonist resulted in increased weight loss and mortality ofinfected mice. Conversely, the PAR1 antagoni... More
Human metapneumovirus (hMPV) infection causes acute respiratory tract infections (RTI) which can result inhospitalization 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, therole of protease-activated receptors (PAR) in inflammation, coagulation and infection processes has been of growinginterest. Herein, the effects of a PAR1 agonist and a PAR1 antagonist on hMPV infection were investigated inBALB/c mice. Intranasal administration of the PAR1 agonist resulted in increased weight loss and mortality ofinfected mice. Conversely, the PAR1 antagonist was beneficial to hMPV infection by decreasing weight loss andclinical 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 viraltiterswas also observed in the lungs of PAR1 antagonist-treated mice. Despite no apparent direct effect on virusreplication during in vitro experiments, an important role for PAR1 in the regulation of furin expression in the lungswas shown for the first time. Further experiments indicated that the hMPV fusion protein can be cleaved by furin thussuggesting 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 ofparamyxovirus infections.
