Animals; Cell Line; Epithelial Cells; Gene Expression Profiling; Genes, Reporter; Humans; Influenza, Human; Lung; Mice; Mice, Inbred C57BL; MicroRNAs; Orthomyxoviridae; RNA Processing, Post-Transcriptional; RNA, Messenger; Signal Transduction; TNF Receptor-Associated Factor 6; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; Viral Load; Virus Replication
Antiviral responses must rapidly defend against infection while minimizing inflammatory damage, but the mechanisms that regulate the magnitude of response within an infected cell are not well understood. miRNAs are small non-coding RNAs that suppress protein levels by binding target sequences on their cognate mRNA. Here, we identify miR-144 as a negative regulator of the host antiviral response. Ectopic expression of miR-144 resulted in increased replication of three RNA viruses in primary mouse lung epithelial cells: influenza virus, EMCV, and VSV. We identified the transcriptional network regulated by miR-144 and demonstrate that miR-144 post-transcriptionally suppresses TRAF6 levels. In vivo ablation of miR-144 reduced influenza virus replication in the lung and disease severity. These data suggest that miR-144 reduces the antiviral response by attenuating the TRAF6-IRF7 pathway to alter the cellular antiviral transcriptional landscape.
Rosenberger, Carrie M; Podyminogin, Rebecca L; Diercks, Alan H; Treuting, Piper M; Peschon, Jacques J; Rodriguez, David; Gundapuneni, Madhumati; Weiss, Mitchell J; and Aderem, Alan, "miR-144 attenuates the host response to influenza virus by targeting the TRAF6-IRF7 signaling axis." (2017). Articles, Abstracts, and Reports. 1598.