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

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.

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2013-05-01
2024-03-29
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References

  1. Bartel D. P. 2009; MicroRNAs: target recognition and regulatory functions. Cell 136:215–233 [View Article][PubMed]
    [Google Scholar]
  2. Buggele W. A., Johnson K. E., Horvath C. M. 2012; Influenza A virus infection of human respiratory cells induces primary microRNA expression. J Biol Chem 287:31027–31040 [View Article][PubMed]
    [Google Scholar]
  3. Cameron J. E., Yin Q., Fewell C., Lacey M., McBride J., Wang X., Lin Z., Schaefer B. C., Flemington E. K. 2008; Epstein–Barr virus latent membrane protein 1 induces cellular MicroRNA miR-146a, a modulator of lymphocyte signaling pathways. J Virol 82:1946–1958 [View Article][PubMed]
    [Google Scholar]
  4. Chen J., Yuan L., Fan Q., Su F., Chen Y., Hu S. 2012; Adjuvant effect of docetaxel on the immune responses to influenza A H1N1 vaccine in mice. BMC Immunol 13:36 [View Article][PubMed]
    [Google Scholar]
  5. Edgar R., Domrachev M., Lash A. E. 2002; Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30:207–210 [View Article][PubMed]
    [Google Scholar]
  6. Fornek J. L., Korth M. J., Katze M. G. 2007; Use of functional genomics to understand influenza–host interactions. Adv Virus Res 70:81–100 [View Article][PubMed]
    [Google Scholar]
  7. Friedman R. C., Farh K. K., Burge C. B., Bartel D. P. 2009; Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105 [View Article][PubMed]
    [Google Scholar]
  8. Gao J., Ade A. S., Tarcea V. G., Weymouth T. E., Mirel B. R., Jagadish H. V., States D. J. 2009; Integrating and annotating the interactome using the MiMI plugin for cytoscape. Bioinformatics 25:137–138 [View Article][PubMed]
    [Google Scholar]
  9. Grimson A., Farh K. K.-H., Johnston W. K., Garrett-Engele P., Lim L. P., Bartel D. P. 2007; MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27:91–105 [View Article][PubMed]
    [Google Scholar]
  10. Hermeking H. 2010; The miR-34 family in cancer and apoptosis. Cell Death Differ 17:193–199 [View Article][PubMed]
    [Google Scholar]
  11. Huang J., Wang F., Argyris E., Chen K., Liang Z., Tian H., Huang W., Squires K., Verlinghieri G., Zhang H. 2007; Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat Med 13:1241–1247 [View Article][PubMed]
    [Google Scholar]
  12. Jopling C. L., Yi M., Lancaster A. M., Lemon S. M., Sarnow P. 2005; Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 309:1577–1581 [View Article][PubMed]
    [Google Scholar]
  13. Josset L., Frobert E., Rosa-Calatrava M. 2008; Influenza A replication and host nuclear compartments: many changes and many questions. J Clin Virol 43:381–390 [View Article][PubMed]
    [Google Scholar]
  14. Josset L., Textoris J., Loriod B., Ferraris O., Moules V., Lina B., N’guyen C., Diaz J. J., Rosa-Calatrava M. 2010; Gene expression signature-based screening identifies new broadly effective influenza A antivirals. PLoS ONE 5:e13169 [View Article][PubMed]
    [Google Scholar]
  15. Kash J. C., Tumpey T. M., Proll S. C., Carter V., Perwitasari O., Thomas M. J., Basler C. F., Palese P., Taubenberger J. K. other authors 2006; Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature 443:578–581[PubMed]
    [Google Scholar]
  16. Kobasa D., Jones S. M., Shinya K., Kash J. C., Copps J., Ebihara H., Hatta Y., Hyun Kim J., Halfmann P. other authors 2007; Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445:319–323 [View Article][PubMed]
    [Google Scholar]
  17. Lecellier C. H., Dunoyer P., Arar K., Lehmann-Che J., Eyquem S., Himber C., Saïb A., Voinnet O. 2005; A cellular microRNA mediates antiviral defense in human cells. Science 308:557–560 [View Article][PubMed]
    [Google Scholar]
  18. Lewis B. P., Burge C. B., Bartel D. P. 2005; Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20 [View Article][PubMed]
    [Google Scholar]
  19. Li Y., Chan E. Y., Li J., Ni C., Peng X., Rosenzweig E., Tumpey T. M., Katze M. G. 2010a; MicroRNA expression and virulence in pandemic influenza virus-infected mice. J Virol 84:3023–3032 [View Article][PubMed]
    [Google Scholar]
  20. Li L., Chen X. P., Li Y. J. 2010b; MicroRNA-146a and human disease. Scand J Immunol 71:227–231 [View Article][PubMed]
    [Google Scholar]
  21. Li Y., Li J., Belisle S., Baskin C. R., Tumpey T. M., Katze M. G. 2011; Differential microRNA expression and virulence of avian, 1918 reassortant, and reconstructed 1918 influenza A viruses. Virology 421:105–113 [View Article][PubMed]
    [Google Scholar]
  22. Loveday E. K., Svinti V., Diederich S., Pasick J., Jean F. 2012; Temporal- and strain-specific host microRNA molecular signatures associated with swine-origin H1N1 and avian-origin H7N7 influenza A virus infection. J Virol 86:6109–6122 [View Article][PubMed]
    [Google Scholar]
  23. Ma Y. J., Yang J., Fan X. L., Zhao H. B., Hu W., Li Z. P., Yu G. C., Ding X. R., Wang J. Z. other authors 2012; Cellular microRNA let-7c inhibits M1 protein expression of the H1N1 influenza A virus in infected human lung epithelial cells. J Cell Mol Med 16:2539–2546 [View Article][PubMed]
    [Google Scholar]
  24. Maere S., Heymans K., Kuiper M. 2005; BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 21:3448–3449 [View Article][PubMed]
    [Google Scholar]
  25. Matskevich A. A., Moelling K. 2007; Dicer is involved in protection against influenza A virus infection. J Gen Virol 88:2627–2635 [View Article][PubMed]
    [Google Scholar]
  26. Neumann G., Kawaoka Y. 2011; The first influenza pandemic of the new millennium. Influenza Other Respir Viruses 5:157–166 [View Article][PubMed]
    [Google Scholar]
  27. Otsuka M., Jing Q., Georgel P., New L., Chen J., Mols J., Kang Y. J., Jiang Z., Du X. other authors 2007; Hypersusceptibility to vesicular stomatitis virus infection in Dicer1-deficient mice is due to impaired miR24 and miR93 expression. Immunity 27:123–134 [View Article][PubMed]
    [Google Scholar]
  28. Paik J. H., Jang J. Y., Jeon Y. K., Kim W. Y., Kim T. M., Heo D. S., Kim C. W. 2011; MicroRNA-146a downregulates NFκB activity via targeting TRAF6 and functions as a tumor suppressor having strong prognostic implications in NK/T cell lymphoma. Clin Cancer Res 17:4761–4771 [View Article][PubMed]
    [Google Scholar]
  29. Palese P. (editor) ( 2007 Orthomyxoviridae, 5th edn. Philadelphia, PA: Lippincott Williams & Wilkins;
    [Google Scholar]
  30. Pedersen I. M., Cheng G., Wieland S., Volinia S., Croce C. M., Chisari F. V., David M. 2007; Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449:919–922 [View Article][PubMed]
    [Google Scholar]
  31. Peng X., Gralinski L., Ferris M. T., Frieman M. B., Thomas M. J., Proll S., Korth M. J., Tisoncik J. R., Heise M. other authors 2011; Integrative deep sequencing of the mouse lung transcriptome reveals differential expression of diverse classes of small RNAs in response to respiratory virus infection. MBio 2:e00198-11 [View Article][PubMed]
    [Google Scholar]
  32. Pichler K., Schneider G., Grassmann R. 2008; MicroRNA miR-146a and further oncogenesis-related cellular microRNAs are dysregulated in HTLV-1-transformed T lymphocytes. Retrovirology 5:100 [View Article][PubMed]
    [Google Scholar]
  33. Schmolke M., Viemann D., Roth J., Ludwig S. 2009; Essential impact of NF-kappaB signaling on the H5N1 influenza A virus-induced transcriptome. J Immunol 183:5180–5189 [CrossRef]
    [Google Scholar]
  34. Skalsky R. L., Cullen B. R. 2010; Viruses, microRNAs, and host interactions. Annu Rev Microbiol 64:123–141 [View Article][PubMed]
    [Google Scholar]
  35. Smoot M. E., Ono K., Ruscheinski J., Wang P. L., Ideker T. 2011; Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics 27:431–432 [View Article][PubMed]
    [Google Scholar]
  36. Song L., Liu H., Gao S., Jiang W., Huang W. 2010; Cellular microRNAs inhibit replication of the H1N1 influenza A virus in infected cells. J Virol 84:8849–8860 [View Article][PubMed]
    [Google Scholar]
  37. Taganov K. D., Boldin M. P., Chang K. J., Baltimore D. 2006; NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 103:12481–12486 [View Article][PubMed]
    [Google Scholar]
  38. Terrier O., Josset L., Textoris J., Marcel V., Cartet G., Ferraris O., N’guyen C., Lina B., Diaz J. J. other authors 2011; Cellular transcriptional profiling in human lung epithelial cells infected by different subtypes of influenza A viruses reveals an overall down-regulation of the host p53 pathway. Virol J 8:285 [View Article][PubMed]
    [Google Scholar]
  39. Tomita M., Tanaka Y., Mori N. 2012; MicroRNA miR-146a is induced by HTLV-1 tax and increases the growth of HTLV-1-infected T-cells. Int J Cancer 130:2300–2309 [View Article][PubMed]
    [Google Scholar]
  40. Tong S., Li Y., Rivailler P., Conrardy C., Castillo D. A., Chen L. M., Recuenco S., Ellison J. A., Davis C. T. other authors 2012; A distinct lineage of influenza A virus from bats. Proc Natl Acad Sci U S A 109:4269–4274[PubMed] [CrossRef]
    [Google Scholar]
  41. Tsitsiou E., Lindsay M. A. 2009; microRNAs and the immune response. Curr Opin Pharmacol 9:514–520 [View Article][PubMed]
    [Google Scholar]
  42. Wang Y., Lee C. G. 2009; MicroRNA and cancer – focus on apoptosis. J Cell Mol Med 13:12–23 [View Article][PubMed]
    [Google Scholar]
  43. Wang Y., Brahmakshatriya V., Zhu H., Lupiani B., Reddy S. M., Yoon B. J., Gunaratne P. H., Kim J. H., Chen R. other authors 2009; Identification of differentially expressed miRNAs in chicken lung and trachea with avian influenza virus infection by a deep sequencing approach. BMC Genomics 10:512 [View Article][PubMed]
    [Google Scholar]
  44. Wang Y., Brahmakshatriya V., Lupiani B., Reddy S. M., Soibam B., Benham A. L., Gunaratne P., Liu H. C., Trakooljul N. other authors 2012; Integrated analysis of microRNA expression and mRNA transcriptome in lungs of avian influenza virus infected broilers. BMC Genomics 13:278 [View Article][PubMed]
    [Google Scholar]
  45. Wurzer W. J., Ehrhardt C., Pleschka S., Berberich-Siebelt F., Wolff T., Walczak H., Planz O., Ludwig S. 2004; NF-kappaB-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas/FasL is crucial for efficient influenza virus propagation. J Biol Chem 279:30931–30937 [View Article][PubMed]
    [Google Scholar]
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