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-Dependent Pathway1
,¶
* Unité de Virologie et Immunologie Moléculaires, Unité de Recherche 892, Institut National de la Recherche Agronomique (INRA), Domaine de Vilvert, Jouy-en-Josas, France;
Unité d’Infectiologie Animale et Santé Publique, Unité de Recherche 1282, Infectiologie Animale et Santé Publique, INRA, Centre de Recherche de Tours, Nouzilly France;
Johnson and Johnson Pharmaceutical Research and Development, Spring House, PA 19477;
INRA, Unité Mixte de Recherche 1225, Université de Toulouse, Ecole Nationale Vétérinaire Toulouse, Toulouse, France;
¶ Université de Toulouse III Paul Sabatier, Toulouse, France;
|| Institut National de la Santé et de la Recherche Médicale, Unité 563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; and
# Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada
Protease-activated receptor-2 (PAR2), a receptor highly expressed in the respiratory tract, can influence inflammation at mucosal surfaces. Although the effects of PAR2 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 PAR2 in influenza pathogenesis in vitro and in vivo. In vitro, stimulation of PAR2 on epithelial cells inhibited influenza virus type A (IAV) replication through the production of IFN-
. In vivo, stimulation of PAR2 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- production and a decreased presence of neutrophils and RANTES release in bronchoalveolar fluids. More importantly, the protective effect of the PAR2 agonist was totally abrogated in IFN- -deficient mice. Finally, compared with wild-type mice, PAR2-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- levels were observed in the bronchoalveolar lavages. Collectively, these results showed that PAR2 plays a protective role during IAV infection through IFN- production and decreased excessive recruitment of inflammatory cells to lung alveoli.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Canadian Institute of Health Research (to N.V.), the Foundation Bettencourt-Schueller, and the Institut National de la Santé et de la Recherche Médicale-Avenir Program (to N.V.), as well as by the Projet Transversal de Recherche INRA-Institut Pasteur (to B.R.) and the Agence Nationale de la Recherche (ANR) (to N.V. and B.R.). K.K. and E.M. are recipients of fellowships from the ANR and the Region Ile de France, respectively.
2 Address correspondence and reprint requests to Dr. Béatrice Riteau, Unité de Virologie et Immunologie Moléculaires, Unité de Recherche 892, Institut National de la Recherche Agronomique, Domaine de Vilvert, 78352 Jouy-en-Josas, France. E-mail address: beatrice.riteau{at}jouy.inra.fr
3 Abbreviations used in this paper: IAV, influenza virus type A; BALF, bronchoalveolar lavage fluid; PAR, protease-activated receptor.
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