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NS1 Protein of Influenza A Virus Inhibits the Function of Intracytoplasmic Pathogen Sensor, RIG-I

Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia; and Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan

Correspondence and requests for reprints should be addressed to Dr. Suryaprakash Sambhara, Centers for Disease Control and Prevention, 1600 Clifton Road, MS: G16, Atlanta, GA 30333. E-mail: ssambhara{at}cdc.gov

Retinoic acid–inducible gene I (RIG-I) has recently been identified as one of the key intracellular sensors of virus infection. RIG-I binds to cytosolic double-stranded RNA and initiates a signaling cascade that leads to the activation of transcription factors required for expression of type I interferon (IFN-I). Previous evidence suggests that nonstructural protein 1 (NS1) encoded by influenza A virus (IAV) suppresses IFN-I secretion in virus-infected cells by an unknown mechanism. In the present study, we demonstrate that RIG-I is required for induction of IFN-I in an IAV-infected human lung epithelial cell line. Knockdown of RIG-I expression by RNA interference greatly impairs production of IFN- in cells infected with different strains of wild-type IAV. Furthermore, co-expression of IAV NS1 down-regulates production of IFN- induced by RIG-I agonists, and ectopic expression of RIG-I inhibits the replication of IAV. These results provide further information on the mechanism by which IAV NS1 antagonizes the host antiviral response.

CLINICAL RELEVANCE Our findings indicate the potential clinical utility of RIG-I–based therapeutic strategies to prevent and treat infections caused by seasonal and pandemic influenza viruses.

 

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