For cytoplasm replicating RNA viruses, this involves detection of viral RNA by RIG-I-like receptors (RLRs), including retinoic acid-induced gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) 3, 4. Microbial nucleic acids are important activators of innate immune responses by triggering so-called pattern recognition receptors (PRRs) 1, 2. The innate immune system provides the first response to virus infections and must discriminate cellular (self) from viral (nonself) nucleic acids to mount a protective immune response against the latter. Collectively, our results highlight that (i) virus acquires m 6A in their RNAs as a means of mimicking cellular RNA to avoid detection by innate immunity and (ii) viral RNA m 6A can serve as a target to attenuate hMPV for vaccine purposes. Furthermore, m 6A-deficient rhMPVs triggered higher IFN in vivo and were significantly attenuated in cotton rats yet retained high immunogenicity. Mechanistically, m 6A-deficient virion RNA induces higher expression of RIG-I, binds more efficiently to RIG-I, and facilitates the conformational change of RIG-I, leading to enhanced IFN expression. Inactivating m 6A addition sites with synonymous mutations or demethylase resulted in m 6A deficient recombinant hMPVs and virion RNAs that induced significantly higher expression of type I interferon (IFN) which was dependent on the cytoplasmic RNA sensor RIG-I, not MDA5. We show that hMPV RNAs are m 6A methylated and that viral m 6A methylation promotes hMPV replication and gene expression. Using human metapneumovirus (hMPV) as a model, we demonstrate that m 6A serves as a molecular marker for innate immune discrimination of self from nonself RNAs.
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However, the biological role(s) of viral RNA m 6A remains elusive. Internal N 6-methyladenosine (m 6A) modification is one of the most common and abundant modifications of RNA.