An accessory to the 'Trinity': SR-As are essential pathogen sensors of extracellular dsRNA, mediating entry and leading to subsequent type I IFN responses.
Extracellular RNA is becoming increasingly recognized as a signaling molecule. Virally derived double stranded (ds)RNA released into the extracellular space during virus induced cell lysis acts as a powerful inducer of classical type I interferon (IFN) responses; however, the receptor that mediates this response has not been identified. Class A scavenger receptors (SR-As) are likely candidates due to their cell surface expression and ability to bind nucleic acids. In this study, we investigated a possible role for SR-As in mediating type I IFN responses induced by extracellular dsRNA in fibroblasts, a predominant producer of IFNbeta. Fibroblasts were found to express functional SR-As, even SR-A species thought to be macrophage specific. SR-A specific competitive ligands significantly blocked extracellular dsRNA binding, entry and subsequent interferon stimulated gene (ISG) induction. Candidate SR-As were systematically investigated using RNAi and the most dramatic inhibition in responses was observed when all candidate SR-As were knocked down in unison. Partial inhibition of dsRNA induced antiviral responses was observed in vivo in SR-AI/II(-/-) mice compared with WT controls. The role of SR-As in mediating extracellular dsRNA entry and subsequent induced antiviral responses was observed in both murine and human fibroblasts. SR-As appear to function as 'carriers', facilitating dsRNA entry and delivery to the established dsRNA sensing receptors, specifically TLR3, RIGI and MDA-5. Identifying SR-As as gatekeepers of the cell, mediating innate antiviral responses, represents a novel function for this receptor family and provides insight into how cells recognize danger signals associated with lytic virus infections. Furthermore, the implications of a cell surface receptor capable of recognizing extracellular RNA may exceed beyond viral immunity to mediating other important innate immune functions.
DeWitte-Orr
Stephanie J
SJ
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Collins
Susan E
SE
Bauer
Carla M T
CM
Bowdish
Dawn M
DM
Mossman
Karen L
KL
D000818:Animals; D002460:Cell Line; D005110:Extracellular Space / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology; D055785:Gene Knockdown Techniques; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology; D012330:RNA, Double-Stranded / Q000378:metabolism*; D012367:RNA, Viral / Q000378:metabolism*; D051117:Scavenger Receptors, Class A / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology*
D007370:Interferon Type I; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D051117:Scavenger Receptors, Class A; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3