Host microRNA molecular signatures associated with human H1N1 and H3N2 influenza A viruses reveal an unanticipated antiviral activity for miR-146a

Abstract

While post-transcriptional regulation of gene expression by microRNAs (miRNAs) has been shown to be involved in influenza virus replication cycle, only a few studies have further investigated this aspect in a human cellular model infected with human influenza viruses. In this study, we performed miRNA global profiling in human lung epithelial cells (A549) infected by two different subtypes of human influenza A viruses (H1N1 and H3N2). We identified a common miRNA signature in response to infection by the two different strains, highlighting a pool of five miRNAs commonly deregulated, which are known to be involved in the innate immune response or apoptosis. Among the five miRNA hits, the only upregulated miRNA in response to influenza infection corresponded to miR-146a. Based on a previously published gene expression dataset, we extracted inversely correlated miR-146a target genes and determined their first-level interactants. This functional analysis revealed eight distinct biological processes strongly associated with these interactants: Toll-like receptor pathway, innate immune response, cytokine production and apoptosis. To better understand the biological significance of miR-146a upregulation, using a reporter assay and a specific anti-miR-146a inhibitor, we confirmed that infection increased the endogenous miR-146a promoter activity and that inhibition of miR-146a significantly increased viral propagation. Altogether, our results suggest a functional role of miR-146a in the outcome of influenza infection, at the crossroads of several biological processes.

microRNAs Regulate Host Immune Response and Pathogenesis During Influenza Infection in Rhesus Macaques

“…This observation is in line with previous studies of H5N3 avian influenza infection in broiler chickens, in which miR-18b was upregulated at 4 dpi in lungs of infected chickens compared with noninfected chickens (48). We also observed a trend of increased miR-146b expression, which was previously reported to be increased at 24 h postinfection in human lung epithelial cells (A549) following in vitro infection with H1N1 and H3N2 influenza virus (38,44). Additionally, our studies revealed that miR-20a and miR-451 were upregulated at 28 dpi in PBMCs as previously documented in serum (collected within 14 days from onset of infection) of patients infected with H7N9 influenza and at 8 h following in vitro H1N1 influenza infection of murine DCs, respectively (35,48,56).…”

Human miR-3145 inhibits influenza A viruses replication by targeting and silencing viral PB1 gene

“…The hsa-miR-146a was reported to inhibit the replication of H1N1 and H3N2 subtypes of influenza A viruses. 20 Ma et al also verified that human miRNA let-7c can regulate the M1 expression of H1N1 influenza virus. 21 Hsa-miR-26a, which was predicted to target the H1N1 influenza virus in our study, was also reported to inhibit the replication of the H1N1 subtype in MDCK cells.…”

Viral and bacterial co-infection in severe pneumonia triggers innate immune responses and specifically enhances IP-10: a translational study

“…So far, no studies have yet focused on the intracellular mechanisms that regulate IP-10 in human blood leukocytes during mixed IAV and SP infection. Several studies indicated that host non-coding small RNAs (including microRNAs) may function as immunomodulators by regulating several pivotal intracellular processes, such as the innate immune response27 and antiviral activity2829; both of these processes are closely related to toll-like receptor (TLR) signaling pathways.…”