miR-144 is a negative regulator of the host antiviral response (158.10)

Abstract

Antiviral responses must be regulated to rapidly defend against infection while minimizing inflammatory damage, but the mechanisms for establishing the magnitude of response within an infected cell are not well understood. microRNAs are post-transcriptional regulators that are attractive candidates for fine tuning the magnitude of the immune response. We identify miR-144 as a negative regulator of the host antiviral response in the lung. We observed that miR-144 expression resulted in increased replication of influenza, EMCV, and VSV in primary mouse lung epithelial cells. We employed a systems biology approach to identify the transcriptional network regulated by miR-144 and demonstrate that it controls the TRAF6/IRF7 antiviral response by post-transcriptionally suppressing TRAF6 expression. Infection of IRF7-null mice revealed that IRF7 is necessary for normal expression of the network of genes that is perturbed by miR-144. Ectopic IRF7 expression restored the antiviral capacity of cells over-expressing miR-144 and reducing TRAF6 levels using shRNAs recapitulated the miR-144 phenotype. In vivo ablation of miR-144 resulted in reduced influenza replication within the lung. These data suggest that miR-144 regulates activation of the IRF7 pathway, thereby creating an exquisitely controlled antiviral response.