Date Published: April 5, 2017
Publisher: Public Library of Science
Author(s): Carrie M. Rosenberger, Rebecca L. Podyminogin, Alan H. Diercks, Piper M. Treuting, Jacques J. Peschon, David Rodriguez, Madhumati Gundapuneni, Mitchell J. Weiss, Alan Aderem, Carolina B. Lopez.
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.
Viruses co-opt host cellular processes in order to replicate, and pathogenicity often correlates with growth rate. The best-characterized antiviral program is regulated by type I interferons, which restricts multiple aspects of the viral life cycle (reviewed in [1–3]). An antiviral response program expressed at a level appropriate to the pathogenicity of the virus can effectively control infection. In contrast, an inadequate response will fail to restrain viral replication while an exaggerated inflammatory response can itself cause damage to the host. Ensuring rapid yet measured antiviral responses at mucosal surfaces, which require a threshold that permits containment of pathogenic insults yet tolerates benign foreign stimuli, is particularly important. In the case of influenza infection, progeny virions can be produced within 6 hours, necessitating a rapid response to quell the infection without triggering excessive inflammation that would compromise airway function.
We have demonstrated microRNA attenuation of the host antiviral response using a miRNA knockout mouse and in vitro models. Reciprocal data obtained from gain- and loss-of-function studies shows that miR-144 modulates an antiviral transcriptional network within lung epithelial cells. The predominant effect of miR-144 deficiency was to decrease viral load rather than modulate inflammatory responses within the virus-infected lung, and better control of very early viral replication within epithelial cells significantly decreased morbidity. We employed primary lung epithelial cells and cell lines since they are a relevant replicative niche for influenza virus, and ectopically expressed miR-144 at physiological levels as a strategy to identify biologically relevant targets of miR-144. miR-144 also increased virion production following infection with VSV, a negative-sense single-stranded RNA viruses, and EMCV, a positive-sense ssRNA encephalomyocarditis virus, indicating that the effect of miR-144 is not restricted to influenza virus.