An accessory to the 'Trinity': SR-As are essential pathogen sensors of extracellular dsRNA, mediating entry and leading to subsequent type I IFN responses

• Published in: PLoS pathogens Vol. 6; no. 3; p. e1000829
• Main Authors: DeWitte-Orr, Stephanie J, Collins, Susan E, Bauer, Carla M T, Bowdish, Dawn M, Mossman, Karen L
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.03.2010; Public Library of Science (PLoS)
• Subjects: Animals; Cell Line; Development and progression; Extracellular Space - genetics; Fibroblasts - cytology; Fluorides; Gene Knockdown Techniques; Genetic aspects; Humans; Immune response; Immune system; Immunology/Immunity to Infections; Immunology/Innate Immunity; Infections; Infectious Diseases/Viral Infections; Interferon; Interferon Type I - metabolism; Medical research; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Monocytes - cytology; NOD-like receptors; Physiological aspects; RNA; RNA, Double-Stranded - metabolism; RNA, Viral - metabolism; Scavenger Receptors, Class A - genetics; Scavenger Receptors, Class A - immunology; Scavenger Receptors, Class A - metabolism; Sensors; Statistical analysis; Toll-Like Receptor 3 - immunology; Viral infections; Virology/Host Antiviral Responses; Virus diseases; Virus Diseases - immunology; Canada
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1000829

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.