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Journal of Virology, June 2008, p. 5940-5950, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.02496-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Sulfatide Is Required for Efficient Replication of Influenza A Virus

Department of Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences and Global COE Program for Innovation in Human Health Sciences, Shizuoka 422-8526, Japan,¹ CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan,² Department of Molecular Genetics, Kochi University Medical School, Nankoku, Kochi 783-8505, Japan,³ Department of Tumor Immunology, Tokyo Metropolitan Institute of Medical Science, The Tokyo Metropolitan Organization for Medical Research, 3-18-22, Honkomagome, Bunkyo-Ku, Tokyo 113-8613, Japan,⁴ Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8566, Japan,⁵ Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, 1200 Matsumoto-cho, Kasugai-shi, Aichi 487-8501, Japan⁶

Received 21 November 2007/ Accepted 5 April 2008

Sulfatide is abundantly expressed in various mammalian organs, including the intestines and trachea, in which influenza A viruses (IAVs) replicate. However, the function of sulfatide in IAV infection remains unknown. Sulfatide is synthesized by two transferases, ceramide galactosyltransferase (CGT) and cerebroside sulfotransferase (CST), and is degraded by arylsulfatase A (ASA). In this study, we demonstrated that sulfatide enhanced IAV replication through efficient translocation of the newly synthesized IAV nucleoprotein (NP) from the nucleus to the cytoplasm, by using genetically produced cells in which sulfatide expression was down-regulated by RNA interference against CST mRNA or overexpression of the ASA gene and in which sulfatide expression was up-regulated by overexpression of both the CST and CGT genes. Treatment of IAV-infected cells with an antisulfatide monoclonal antibody (MAb) or an anti-hemagglutinin (HA) MAb, which blocks the binding of IAV and sulfatide, resulted in a significant reduction in IAV replication and accumulation of the viral NP in the nucleus. Furthermore, antisulfatide MAb protected mice against lethal challenge with pathogenic influenza A/WSN/33 (H1N1) virus. These results indicate that association of sulfatide with HA delivered to the cell surface induces translocation of the newly synthesized IAV ribonucleoprotein complexes from the nucleus to the cytoplasm. Our findings provide new insights into IAV replication and suggest new therapeutic strategies.

Published ahead of print on 16 April 2008.