Editors' ChoiceHost-Pathogen Interactions

MicroRNAs that interfere with interferons

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Sci. Signal.  13 Dec 2016:
Vol. 9, Issue 458, pp. ec295
DOI: 10.1126/scisignal.aam5594

Hepatitis C virus (HCV) infects the liver and can cause cirrhosis and liver cancer. Both the ability of patients to naturally clear the infection and the probability of a patient being cured by currently available drug regimens are associated with specific single-nucleotide polymorphisms in IFNL3, a gene that encodes the antiviral cytokine type III interferon λ3. The favorable IFNL3 genotype results in increased expression of interferon-stimulated genes (ISGs) and higher antiviral activity in HCV-infected hepatocytes, overcoming viral suppression of these responses. HCV infection results in host production of microRNAs originating from the introns of host myosin-encoding genes (myomiRs) that suppress type III interferon production. Jarret et al. found that myomiRs were both induced by and also dampened host type I interferon signaling. Huh7 hepatoma cells were transfected with locked nucleic acid (LNA) inhibitors against the myomiRs or nontargeting LNAs and then treated with interferon-β (IFN-β) to mimic the type I IFN production that occurs after viral infection and after treatment with pegylated IFN-α, which is part of the combination therapy against HCV. Inhibiting myomiRs resulted in an increase in transcription of several ISGs only in cells that were both infected with HCV and stimulated with IFN-β. IFNAR1, which encodes a type I interferon receptor subunit, contained multiple predicted miRNA recognition elements for the myomiRs in the 3′ untranslated region. Correspondingly, cells overexpressing myomiRs expressed less IFNAR1, whereas those treated with myomiR inhibitors had less cell-surface IFNAR1, suggesting that the reduction in expression of ISGs was due to the myomiR-mediated suppression of IFNAR1. Induction of myomiRs was specific to HCV infection because infection with three other viruses or generic viral signals did not result in increased expression of the myosin-encoding parent genes, and induction of these genes depended on the presence of actively replicating viruses. Treating HCV-infected cells with type I interferons, but not type III interferons, increased expression of the myosin-encoding parent genes, suggesting that the myomiR effect on type III interferons occurred after the induction of myomiR production by the type I interferon response to infection. These results showed that HCV-induced miroRNAs suppressed host antiviral responses through cross-talk between the type I and type III interferon signaling pathways. Furthermore, these results help explain why individuals with the unfavorable IFNL3 allele are less responsive to treatment with type I interferons.

A. Jarret, A. P. McFarland, S. M. Horner, A. Kell, J. Schwerk, M. Hong, S. Badil, R. C. Joslyn, D. P. Baker, M. Carrington, C. H. Hagedorn, M. Gale Jr., R. Savan, Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling. Nat. Med. 22, 1475–1481 (2016). [PubMed]