Host microRNA molecular signatures associated with human H1N1 and H3N2 influenza A viruses reveal an unanticipated antiviral activity for miR-146a.
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.
Laboratoire de Virologie et Pathologie Humaine VirPath, Equipe VirCell, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
Olivier
O
Terrier
Laboratoire d'Immunologie, UMR CNRS 7278, INSERM U1095, Faculté de Médecine Timone, Marseille, France.
Julien
J
Textoris
Laboratoire de Virologie et Pathologie Humaine VirPath, Equipe VirCell, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
Coralie
C
Carron
Division of Medical Sciences, Centre for Oncology and Molecular Medicine, University of Dundee, Ninewells Hospital, Dundee, Scotland, UK.
Virginie
V
Marcel
Division of Medical Sciences, Centre for Oncology and Molecular Medicine, University of Dundee, Ninewells Hospital, Dundee, Scotland, UK.
Jean-Christophe
JC
Bourdon
Laboratoire de Virologie et Pathologie Humaine VirPath, Equipe VirCell, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.
Manuel
M
Rosa-Calatrava
D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D015536:Down-Regulation; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D020869:Gene Expression Profiling; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics* / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics* / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology / Q000821:virology*; D008168:Lung / Q000166:cytology / Q000821:virology; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015854:Up-Regulation
C542542:MIRN146 microRNA, human; D035683:MicroRNAs