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Cutting Edge: Innate Immune Response Triggered by Influenza A Virus Is Negatively Regulated by SOCS1 and SOCS3 through a RIG-I/IFNAR1-Dependent Pathway¹

Julien Pothlichet^*,, Michel Chignard^*, and Mustapha Si-Tahar^2,*,

^* Institut Pasteur, Unité Défense Innée et Inflammation, Paris, France; and Institut National de la Santé et de la Recherche Médicale, Unité 874, Paris, France

Influenza A virus (IAV) triggers a contagious respiratory disease that produces considerable lethality. Although this lethality is likely due to an excessive host inflammatory response, the negative feedback mechanisms aimed at regulating such a response are unknown. In this study, we investigated the role of the eight "suppressor of cytokine signaling" (SOCS) regulatory proteins in IAV-triggered cytokine expression in human respiratory epithelial cells. SOCS1 to SOCS7, but not cytokine-inducible Src homology 2-containing protein (CIS), are constitutively expressed in these cells and only SOCS1 and SOCS3 expressions are up-regulated upon IAV challenge. Using distinct approaches affecting the expression and/or the function of the IFNβ receptor (IFNAR)1, the viral sensors TLR3 and retinoic acid-inducible gene I (RIG-I) as well as the mitochondrial antiviral signaling protein (MAVS, a RIG-I signaling intermediate), we demonstrated that SOCS1 and SOCS3 up-regulation requires a TLR3-independent, RIG-I/MAVS/IFNAR1-dependent pathway. Importantly, by using vectors overexpressing SOCS1 and SOCS3 we revealed that while both molecules inhibit antiviral responses, they differentially modulate inflammatory signaling pathways.

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 study was partially funded by the Institut Pasteur through "Programme Transversal de Recherche" (PTR no.186). J.P. was financially supported by the French association "Vaincre la mucoviscidose".

² Address correspondence and reprint requests to Dr. M. Si-Tahar, Unité Défense Innée et Inflammation, INSERM U874, Institut Pasteur, 25 Rue du Dr. Roux, 75015 Paris, France. E-mail address: sitahar{at}pasteur.fr

³ Abbreviations used in this paper: IAV, influenza A virus; CIS, cytokine-inducible Src homology 2-containing protein; IFNAR1, IFNβ receptor 1; IRF-3, IFN regulatory factor 3; MAVS, mitochondrial antiviral signaling protein; MOI, multiplicity of infection; qRT-PCR, quantitative RT-PCR; RIG-I, retinoic acid-inducible gene-I; siRNA, short interfering RNA; SOCS, suppressor of cytokine signaling protein.

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