2024-03-28T17:32:08Zhttps://eprints.lib.hokudai.ac.jp/dspace-oai/requestoai:eprints.lib.hokudai.ac.jp:2115/391302022-11-17T02:08:08Zhdl_2115_20055hdl_2115_8527Soluble G protein of respiratory syncytial virus inhibits Toll-like receptor 3/4-mediated IFN-beta inductionBlocking TLR-TICAM-1 pathway by RSV sGShingai, MasashiAzuma, MasahiroEbihara, TakashiSasai, MiwaFunami, KenjiAyata, MinoruOgura, HisashiTsutsumi, HiroyukiMatsumoto, MisakoSeya, TsukasaToll-like receptorTICAM-1 (TRIF)respiratory syncytial virustype I interferonsdendritic cells491Monocyte-derived dendritic cells (mDCs) recognize viral RNA extrinsically by TLR3 on the membrane and intrinsically RIG-I/MDA5 in the cytoplasm to induce type I interferons (IFNs) and mDC maturation. When mDCs were treated with live or UV-irradiated respiratory syncytial virus (RSV), early (~4 h) induction of IFN-β detected 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 Abs 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 protein remains undetermined, G proteins may neutralize the F protein function that promotes IFN-mediated mDC modulation via TLR4 and may cause insufficient raising cell-mediated immunity against RSV.Oxford Univ PressJournal Articleapplication/pdfhttp://hdl.handle.net/2115/39130https://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/39130/1/RSV_3rd.pdf0953-81781460-2377AA10730708International Immunology209116911802008-09enginfo:pmid/18611945info:doi/10.1093/intimm/dxn074This is a pre-copy-editing, author-produced PDF of an article accepted for publication in "International Immunology" following peer review. The definitive publisher-authenticated version "International Immunology 2008 20(9):1169-1180" is available online at: http://dx.doi.org/10.1093/intimm/dxn074author