Abstract
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 IFNβ. 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.
Highlights
There is a ‘trinity’ of pattern recognition receptors (PRRs) used by the innate immune system to sense pathogens
Cells can die by lysis during virus infections, and the intracellular dsRNA is released into the extracellular space
This dsRNA is stable in the extracellular milieu, and is able to function as a signaling molecule, detected by neighboring cells. This has been observed experimentally, as extracellular dsRNA has been used for years to trigger host antiviral responses
Summary
There is a ‘trinity’ of pattern recognition receptors (PRRs) used by the innate immune system to sense pathogens. All three sensor families have been implicated in innate antiviral responses, with members of each family being able to recognize viral double-stranded (ds) RNA, a pathogen associated molecular pattern (PAMP) and a powerful inducer of both innate and adaptive immune responses Cellular localization of these dsRNA sensors differs; TLR3 is endosomal while the RLRs and NLRs (RIG-I/MDA-5/LGP2 and Nalp respectively) are cytoplasmic [2,3,4]. RIG-I, MDA-5 and LGP2 recognize dsRNA in the cytoplasm and while LPG2 lacks signaling capability [6], RIG-I and MDA-5 signal through interferon (IFN)-b promoter stimulator 1 (IPS-1), an adaptor molecule associated with the mitochondria [7] These pathways lead to the activation of transcription factors, including
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