title: Identification of a novel pathway essential for the immediate-early, interferon-independent antiviral response to enveloped virions.
abstract: Viral infection elicits the activation of numerous cellular signal transduction pathways, leading to the induction of both innate and adaptive immunity. Previously we showed that entry of virion particles from a diverse array of enveloped virus families was capable of eliciting an interferon regulatory factor 3 (IRF-3)-mediated antiviral state in human fibroblasts in the absence of interferon production. Here we show that extracellular regulated kinase 1/2, p38 mitogen-activated protein kinase, and Jun N-terminal kinase/stress-activated protein kinase activities are not required for antiviral state induction. In contrast, treatment of cells with LY294002, an inhibitor of the phosphoinositide 3-kinase (PI3 kinase) family, prevents the induction of interferon-stimulated gene 56 (ISG56) and an antiviral response upon entry of virus particles. However, the prototypic class I p85/p110 PI3 kinase and its downstream effector Akt/PKB are dispensable for ISG and antiviral state induction. Furthermore, DNA-PK and PAK1, LY294002-sensitive members of the PI3 kinase family shown previously to be involved in IRF-3 activation, are also dispensable for ISG and antiviral state induction. The LY294002 inhibitor fails to prevent IRF-3 homodimerization or nuclear translocation upon virus particle entry. Together, these data suggest that virus entry triggers an innate antiviral response that requires the activity of a novel PI3 kinase family member.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Centre for Gene Therapeutics, Michael DeGroote Centre for Learning and Discovery, Room 5026, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Noyce
authors.forename: Susan E
authors.initials: SE
authors.lastname: Collins
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mossman
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D017781:Genes, Immediate-Early / Q000502:physiology*; D007372:Interferons / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000502:physiology*; D014709:Vero Cells; D014771:Virion / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000502:physiology
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors