Protective role for protease-activated receptor-2 against influenza virus pathogenesis via an IFN-gamma-dependent pathway.
Protease-activated receptor-2 (PAR(2)), a receptor highly expressed in the respiratory tract, can influence inflammation at mucosal surfaces. Although the effects of PAR(2) in the innate immune response to bacterial infection have been documented, knowledge of its role in the context of viral infection is lacking. We thus investigated the role of PAR(2) in influenza pathogenesis in vitro and in vivo. In vitro, stimulation of PAR(2) on epithelial cells inhibited influenza virus type A (IAV) replication through the production of IFN-gamma. In vivo, stimulation of PAR(2) using specific agonists protected mice from IAV-induced acute lung injury and death. This effect correlated with an increased clearance of IAV in the lungs associated with increased IFN- gamma production and a decreased presence of neutrophils and RANTES release in bronchoalveolar fluids. More importantly, the protective effect of the PAR(2) agonist was totally abrogated in IFN- gamma-deficient mice. Finally, compared with wild-type mice, PAR(2)-deficient mice were more susceptible to IAV infection and displayed more severe lung inflammation. In these mice higher neutrophil counts and increased RANTES concentration but decreased IFN- gamma levels were observed in the bronchoalveolar lavages. Collectively, these results showed that PAR(2) plays a protective role during IAV infection through IFN-gamma production and decreased excessive recruitment of inflammatory cells to lung alveoli.
Khoufache
Khaled
K
Unité de Virologie et Immunologie Moléculaires, Unité de Recherche 892, Institut National de la Recherche Agronomique, Domaine de Vilvert, Jouy-en-Josas, France.
LeBouder
Fanny
F
Morello
Eric
E
Laurent
Fabrice
F
Riffault
Sabine
S
Andrade-Gordon
Patricia
P
Boullier
Severine
S
Rousset
Perrine
P
Vergnolle
Nathalie
N
Riteau
Béatrice
B
D000818:Animals; D002460:Cell Line; D004285:Dogs; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000472:pathogenicity*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D044464:Receptor, PAR-2 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D015854:Up-Regulation
D044464:Receptor, PAR-2; D007371:Interferon-gamma