title: Class A Scavenger Receptor-Mediated Double-Stranded RNA Internalization Is Independent of Innate Antiviral Signaling and Does Not Require Phosphatidylinositol 3-Kinase Activity.
abstract: dsRNA is a potent trigger of innate immune signaling, eliciting effects within virally infected cells and after release from dying cells. Given its inherent stability, extracellular dsRNA induces both local and systemic effects. Although the class A scavenger receptors (SR-As) mediate dsRNA entry, it is unknown whether they contribute to signaling beyond ligand internalization. In this study, we investigated whether SR-As contribute to innate immune signaling independent of the classic TLR and retinoic acid-inducible gene-I-like receptor (RLR) pathways. We generated a stable A549 human epithelial cell line with inducible expression of the hepatitis C virus protease NS3/4A, which efficiently cleaves TRIF and IFN-β promoter stimulator 1, adaptors for TLR3 and the RLRs, respectively. Cells expressing NS3/4A and TLR3/MyD88/IFN-β promoter stimulator 1(-/-) mouse embryonic fibroblasts completely lacked antiviral activity to extracellular dsRNA relative to control cells, suggesting that SR-As do not possess signaling capacity independent of TLR3 or the RLRs. Previous studies implicated PI3K signaling in SR-A-mediated activities and in downstream production of type I IFN. We found that SR-A-mediated dsRNA internalization occurs independent of PI3K activation, whereas downstream signaling leading to IFN production was partially dependent on PI3K activity. Overall, these findings suggest that SR-A-mediated dsRNA internalization is independent of innate antiviral signaling.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Center, Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada L8S 4K1;
authors.forename: Srinivas
authors.initials: S
authors.lastname: Nellimarla
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Center, Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada L8S 4K1;
authors.forename: Kaushal
authors.initials: K
authors.lastname: Baid
authors.affiliation: Department of Immunology, Center for Innate Immunity and Immune Disease, School of Medicine, University of Washington, Seattle, WA 98109; and.
authors.forename: Yueh-Ming
authors.initials: YM
authors.lastname: Loo
authors.affiliation: Department of Immunology, Center for Innate Immunity and Immune Disease, School of Medicine, University of Washington, Seattle, WA 98109; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Center, Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada L8S 4K1;
authors.forename: Dawn M E
authors.initials: DM
authors.lastname: Bowdish
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Center, Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada L8S 4K1; Department of Biochemistry and Biomedical Sciences, McMaster Immunology Research Center, Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada L8S 4K1 mossk@mcmaster.ca.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mossman
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology; D000818:Animals; D002460:Cell Line; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology*; D012330:RNA, Double-Stranded / Q000235:genetics / Q000276:immunology*; D012367:RNA, Viral / Q000276:immunology*; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000276:immunology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D053594:Myeloid Differentiation Factor 88; D019869:Phosphatidylinositol 3-Kinases; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D051117:Scavenger Receptors, Class A; D051196:Toll-Like Receptor 3; D017361:Viral Nonstructural Proteins; C507780:Myd88 protein, mouse; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C080106:NS4A protein, flavivirus; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse