RNA:DNA hybrids are a novel molecular pattern sensed by TLR9

Abstract

The sensing of nucleic acids by receptors of the innate immune system is a key component of antimicrobial immunity. RNA:DNA hybrids, as essential intracellular replication intermediates generated during infection, could therefore represent a class of previously uncharacterised pathogen‐associated molecular patterns sensed by pattern recognition receptors. Here we establish that RNA:DNA hybrids containing viral‐derived sequences efficiently induce pro‐inflammatory cytokine and antiviral type I interferon production in dendritic cells. We demonstrate that MyD88‐dependent signalling is essential for this cytokine response and identify TLR9 as a specific sensor of RNA:DNA hybrids. Hybrids therefore represent a novel molecular pattern sensed by the innate immune system and so could play an important role in host response to viruses and the pathogenesis of autoimmune disease. Nucleic acids are potent ligands for the pattern recognition receptors of the innate immune system. In this work, RNA:DNA hybrids are established to be a novel class of immunostimulatory nucleic acid, binding and activating intracellular TLR9 in dendritic cells. TLR9 may therefore have a wider role in host response to microbial infection, including the sensing of RNA:DNA hybrid replication intermediates. TLR9, classically known as cytokine‐inducing sensor of bacterial DNA, gains an additional role in detecting RNA:DNA hybrids containing virus‐derived sequences, making them a novel type of pathogen‐associated molecular pattern.

Cited by papers we hold 8

• mRNA vaccines for COVID-19: what, why and how · 2021
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• Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses · 2018
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• RNA/DNA Hybrid Interactome Identifies DXH9 as a Molecular Player in Transcriptional Termination and R-Loop-Associated DNA Damage · 2018
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• Replication and transcription on a collision course: eukaryotic regulation mechanisms and implications for DNA stability. · 2015
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• Genome-wide DNA hypomethylation and RNA:DNA hybrid accumulation in Aicardi–Goutières syndrome · 2015
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• Pattern Recognition and Signaling Mechanisms of RIG-I and MDA5 · 2014
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• Out of Balance: R-loops in Human Disease · 2014
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• Genome-Wide Distribution of RNA-DNA Hybrids Identifies RNase H Targets in tRNA Genes, Retrotransposons and Mitochondria · 2014
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