title: Modulation of protease activated receptor 1 influences human metapneumovirus disease severity in a mouse model.
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.
authors.affiliation: Centre de Recherche en Infectiologie du Centre Hospitalier Universitaire de Québec and Université Laval, Quebec, Canada.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Aerts
authors.forename: Marie-Ève
authors.initials: MÈ
authors.lastname: Hamelin
authors.forename: Chantal
authors.initials: C
authors.lastname: Rhéaume
authors.forename: Sophie
authors.initials: S
authors.lastname: Lavigne
authors.forename: Christian
authors.initials: C
authors.lastname: Couture
authors.forename: Woojin
authors.initials: W
authors.lastname: Kim
authors.forename: Delia
authors.initials: D
authors.lastname: Susan-Resiga
authors.forename: Annik
authors.initials: A
authors.lastname: Prat
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vergnolle
authors.forename: Beatrice
authors.initials: B
authors.lastname: Riteau
authors.forename: Guy
authors.initials: G
authors.lastname: Boivin
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D045683:Furin / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D029121:Metapneumovirus / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018184:Paramyxoviridae Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D044463:Receptor, PAR-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012141:Respiratory Tract Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index
chemical_list: D016207:Cytokines; D044463:Receptor, PAR-1; D045683:Furin