International Immunology Advance Access originally published online on July 8, 2008
International Immunology 2008 20(9):1169-1180; doi:10.1093/intimm/dxn074
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Soluble G protein of respiratory syncytial virus inhibits Toll-like receptor 3/4-mediated IFN-beta induction
1 Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan
2 Department of Virology, Osaka City University, Asahimachi 1-4-3, Abeno-ku, Osaka 545-8585, Japan
3 Department of Pediatrics, Sapporo Medical University, School of Medicine, Minami-1, Nishi-16, Chuoh-ku, Sapporo 060-8543, Japan
4 Present address: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
5 Present address: Section of Immunobiology, Yale University School of Medicine, 300 Cedar Street, TAC S640, New Haven, CT 06520, USA
6 Present address: Medical Research Center, Keio University, Shinanomachi 35, Shinjuku-ku, Tokyo 160-8582, Japan
Correspondence to: T. Seya; E-mail: seya-tu{at}pop.med.hokudai.ac.jp
Monocyte-derived dendritic cells (mDCs) recognize viral RNA extrinsically by Toll-like receptor (TLR) 3 on the membrane and intrinsically retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5) in the cytoplasm to induce type I IFNs and mDC maturation. When mDCs were treated with live or UV-irradiated respiratory syncytial virus (RSV), early (
4 h) induction of IFN-β usually occurs in other virus infections was barely observed. Live RSV subsequently replicated to activate the cytoplasmic IFN-inducing pathway leading to robust type I IFN induction. We found that RSV initial attachment to cells blocked polyI:C-mediated IFN-β induction, and this early IFN-β-modulating event was abrogated by antibodies against envelope proteins of RSV, demonstrating the presence of a IFN-regulatory mode by early RSV attachment to host cells. By IFN-stimulated response element (ISRE) reporter analysis in HEK293 cells, polyI:C- or LPS-mediated ISRE activation was dose dependently inhibited by live and inactive RSV to a similar extent. Of the RSV envelope proteins, simultaneously expressed or exogenously added RSV G or soluble G (sG) proteins inhibited TLR3/4-mediated ISRE activation in HEK293 cells. sG proteins expressed in cells did not affect the RIG-I/MDA5 pathway but inhibited the TLR adaptor TRIF/TICAM-1 pathway for ISRE activation. Finally, extrinsically added sG protein suppressed the production of IFN-β in mDCs. Although the molecular mechanism of this extrinsic functional mode of the RSV G glycoprotein (G protein) remains undetermined, G proteins may neutralize the fusion glycoprotein function that promotes IFN-mediated mDC modulation via TLR4 and may cause insufficient raising cell-mediated immunity against RSV.
Keywords: dendritic cells, respiratory syncytial virus, TICAM-1 (TRIF), Toll-like receptor, type I IFNs
Transmitting editor: T. Takai
Received 20 September 2007, revised 27 May 2008, accepted 9 June 2008.
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