Vesicular stomatitis virus glycoprotein G activates a specific antiviral Toll-like receptor 4-dependent pathway.
We have previously shown that mutations of CD14 or TLR4 impair type I interferon (IFN) production and macrophage survival during infection with vesicular stomatitis virus (VSV). We now report that VSV glycoprotein G (gpG) is essential for the induction of a previously unrecognized CD14/TLR4-dependent response pathway in which the adapter TRAM has predominant importance, absent any need for MyD88 or Mal, and with only a partial requirement for TRIF. Downstream of TRAM, IRF7 activation leads to a type I IFN response. The pathway is utilized by myeloid dendritic cells (mDCs) and macrophages rather than plasmacytoid DCs. This new mode of TLR4 signal transduction, which does not stimulate NF-kappaB activation, reveals the importance of viral protein recognition by mDCs and shows that TLR4 can drive qualitatively different events within the cell in response to different ligands.
Georgel
Philippe
P
Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, USA. philippe.georgel@hemato-ulp.u-strasbg.fr
Jiang
Zhengfan
Z
Kunz
Stefan
S
Janssen
Edith
E
Mols
Johann
J
Hoebe
Kasper
K
Bahram
Siamak
S
Oldstone
Michael B A
MB
Beutler
Bruce
B
D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000096:biosynthesis; D007370:Interferon Type I / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000821:virology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D026901:Membrane Transport Proteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009185:Myelin Proteins / Q000276:immunology; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D011510:Proteolipids / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000276:immunology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000276:immunology*
D033942:Adaptor Proteins, Vesicular Transport; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88; D011510:Proteolipids; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D051197:Toll-Like Receptor 4; D014759:Viral Envelope Proteins; C028391:G protein, vesicular stomatitis virus; C494235:Irf7 protein, mouse; C569026:MAL protein, human; C569027:Mal protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C476416:Ticam2 protein, mouse; C493487:Tlr4 protein, mouse