1887

Abstract

Enterovirus 71 (EV71) has caused major outbreaks of hand, foot and mouth disease. EV71 infections increase the production of many host cytokines and pro-inflammatory factors, including interleukin (IL)-6, IL-10 and COX-2. Some of these molecules could stimulate the signal transducer and activator of transcription 3 (STAT3), which plays a key role in regulating host immune responses and several viral diseases. However, the role of STAT3 in EV71 infection remains unknown. This study found that the phosphorylation levels of STAT3 (p-STAT3) are closely related to EV71 infection. Further experiments revealed that STAT3 exerts an anti-EV71 activity. However, the antiviral activity of STAT3 is partially antagonized by EV71-induced miR-124, which directly targets STAT3 mRNA. Similarly, IL-6R, the α-subunit of the IL-6 receptor complex, exhibits anti-EV71 activity and is directly targeted by the virus-induced miR-124. These results indicate that EV71 can evade host IL-6R- and STAT3-mediated antiviral activities by EV71-induced miR-124. This suggests that controlling miR-124 and the downstream targets, IL-6R and STAT3, might benefit the antiviral treatment of EV71 infection.

Keyword(s): Enterovirus 71 , IL-6R , miRNA-124 and STAT3
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2017-12-01
2024-03-28
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References

  1. Solomon T, Lewthwaite P, Perera D, Cardosa MJ, Mcminn P et al. Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis 2010; 10:778–790 [View Article][PubMed]
    [Google Scholar]
  2. Ooi MH, Wong SC, Lewthwaite P, Cardosa MJ, Solomon T. Clinical features, diagnosis, and management of enterovirus 71. Lancet Neurol 2010; 9:1097–1105 [View Article][PubMed]
    [Google Scholar]
  3. Chang PC, Chen SC, Chen KT. The current status of the disease caused by enterovirus 71 infections: epidemiology, pathogenesis, molecular epidemiology, and vaccine development. Int J Environ Res Public Health 2016; 13:890 [View Article][PubMed]
    [Google Scholar]
  4. Jiang P, Liu Y, Ma HC, Paul AV, Wimmer E. Picornavirus morphogenesis. Microbiol Mol Biol Rev 2014; 78:418–437 [View Article][PubMed]
    [Google Scholar]
  5. Weng KF, Chen LL, Huang PN, Shih SR. Neural pathogenesis of enterovirus 71 infection. Microbes Infect 2010; 12:505–510 [View Article][PubMed]
    [Google Scholar]
  6. Huang HI, Weng KF, Shih SR. Viral and host factors that contribute to pathogenicity of enterovirus 71. Future Microbiol 2012; 7:467–479 [View Article][PubMed]
    [Google Scholar]
  7. Tung WH, Hsieh HL, Yang CM. Enterovirus 71 induces COX-2 expression via MAPKs, NF-kappaB, and AP-1 in SK-N-SH cells: Role of PGE(2) in viral replication. Cell Signal 2010; 22:234–246 [View Article][PubMed]
    [Google Scholar]
  8. Wang SM, Lei HY, Huang KJ, Wu JM, Wang JR et al. Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: roles of cytokines and cellular immune activation in patients with pulmonary edema. J Infect Dis 2003; 188:564–570 [View Article][PubMed]
    [Google Scholar]
  9. Wang SM, Lei HY, Huang MC, Su LY, Lin HC et al. Modulation of cytokine production by intravenous immunoglobulin in patients with enterovirus 71-associated brainstem encephalitis. J Clin Virol 2006; 37:47–52 [View Article][PubMed]
    [Google Scholar]
  10. Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST et al. Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship?. Ann N Y Acad Sci 2009; 1171:59–76 [View Article][PubMed]
    [Google Scholar]
  11. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9:798–809 [View Article][PubMed]
    [Google Scholar]
  12. Tung WH, Lee IT, Hsieh HL, Yang CM. EV71 induces COX-2 expression via c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK/AP-1 and NF-kappaB in rat brain astrocytes. J Cell Physiol 2010; 224:376–386 [View Article][PubMed]
    [Google Scholar]
  13. Akira S, Nishio Y, Inoue M, Wang XJ, Wei S et al. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 1994; 77:63–71 [View Article][PubMed]
    [Google Scholar]
  14. Walter MR. The molecular basis of IL-10 function: from receptor structure to the onset of signaling. Curr Top Microbiol Immunol 2014; 380:191–212 [View Article][PubMed]
    [Google Scholar]
  15. Gao B, Wang H, Lafdil F, Feng D. STAT proteins - key regulators of anti-viral responses, inflammation, and tumorigenesis in the liver. J Hepatol 2012; 57:430–441 [View Article][PubMed]
    [Google Scholar]
  16. Scheller J, Garbers C, Rose-John S. Interleukin-6: from basic biology to selective blockade of pro-inflammatory activities. Semin Immunol 2014; 26:2–12 [View Article][PubMed]
    [Google Scholar]
  17. Regis G, Pensa S, Boselli D, Novelli F, Poli V. Ups and downs: the STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling. Semin Cell Dev Biol 2008; 19:351–359 [View Article][PubMed]
    [Google Scholar]
  18. Kuchipudi SV. The Complex Role of STAT3 in Viral Infections. J Immunol Res 2015; 2015:1–9 [View Article][PubMed]
    [Google Scholar]
  19. Ray JP, Marshall HD, Laidlaw BJ, Staron MM, Kaech SM et al. Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells. Immunity 2014; 40:367–377 [View Article][PubMed]
    [Google Scholar]
  20. Siegel AM, Heimall J, Freeman AF, Hsu AP, Brittain E et al. A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. Immunity 2011; 35:806–818 [View Article][PubMed]
    [Google Scholar]
  21. Skalsky RL, Cullen BR, Viruses CBR. Viruses, microRNAs, and host interactions. Annu Rev Microbiol 2010; 64:123–141 [View Article][PubMed]
    [Google Scholar]
  22. Ho BC, Yu SL, Chen JJ, Chang SY, Yan BS et al. Enterovirus-induced miR-141 contributes to shutoff of host protein translation by targeting the translation initiation factor eIF4E. Cell Host Microbe 2011; 9:58–69 [View Article][PubMed]
    [Google Scholar]
  23. Bian L, Wang Y, Liu Q, Xia J, Long JE. Prediction of signaling pathways involved in enterovirus 71 infection by algorithm analysis based on miRNA profiles and their target genes. Arch Virol 2015; 160:173–182 [View Article][PubMed]
    [Google Scholar]
  24. Cai B, Li J, Wang J, Luo X, Ai J et al. microRNA-124 regulates cardiomyocyte differentiation of bone marrow-derived mesenchymal stem cells via targeting STAT3 signaling. Stem Cells 2012; 30:1746–1755 [View Article][PubMed]
    [Google Scholar]
  25. Hatziapostolou M, Polytarchou C, Aggelidou E, Drakaki A, Poultsides GA et al. An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell 2011; 147:1233–1247 [View Article][PubMed]
    [Google Scholar]
  26. Xiao Y, Wang J, Yan W, Zhou Y, Chen Y et al. Dysregulated miR-124 and miR-200 expression contribute to cholangiocyte proliferation in the cholestatic liver by targeting IL-6/STAT3 signalling. J Hepatol 2015; 62:889–896 [View Article][PubMed]
    [Google Scholar]
  27. Lu J, He YQ, Yi LN, Zan H, Kung HF et al. Viral kinetics of enterovirus 71 in human abdomyosarcoma cells. World J Gastroenterol 2011; 17:4135–4142 [View Article][PubMed]
    [Google Scholar]
  28. Qin Z, Wang PY, Su DF, Liu X. miRNA-124 in Immune System and Immune Disorders. Front Immunol 2016; 7:406 [View Article][PubMed]
    [Google Scholar]
  29. Garbers C, Aparicio-Siegmund S, Rose-John S. The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition. Curr Opin Immunol 2015; 34:75–82 [View Article][PubMed]
    [Google Scholar]
  30. Wolf J, Rose-John S, Garbers C. Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine 2014; 70:11–20 [View Article][PubMed]
    [Google Scholar]
  31. Feng Q, Langereis MA, Lork M, Nguyen M, Hato SV et al. Enterovirus 2Apro targets MDA5 and MAVS in infected cells. J Virol 2014; 88:3369–3378 [View Article][PubMed]
    [Google Scholar]
  32. Lei X, Liu X, Ma Y, Sun Z, Yang Y et al. The 3C protein of enterovirus 71 inhibits retinoid acid-inducible gene I-mediated interferon regulatory factor 3 activation and type I interferon responses. J Virol 2010; 84:8051–8061 [View Article][PubMed]
    [Google Scholar]
  33. Lei X, Xiao X, Xue Q, Jin Q, He B et al. Cleavage of interferon regulatory factor 7 by enterovirus 71 3C suppresses cellular responses. J Virol 2013; 87:1690–1698 [View Article][PubMed]
    [Google Scholar]
  34. Lu J, Yi L, Zhao J, Yu J, Chen Y et al. Enterovirus 71 disrupts interferon signaling by reducing the level of interferon receptor 1. J Virol 2012; 86:3767–3776 [View Article][PubMed]
    [Google Scholar]
  35. Wang B, Xi X, Lei X, Zhang X, Cui S et al. Enterovirus 71 protease 2Apro targets MAVS to inhibit anti-viral type I interferon responses. PLoS Pathog 2013; 9:e1003231 [View Article][PubMed]
    [Google Scholar]
  36. Ho BC, Yang PC, Yu SL, Bc H, Sl Y. MicroRNA and Pathogenesis of Enterovirus Infection. Viruses 2016; 8: [View Article][PubMed]
    [Google Scholar]
  37. Hill ER, Koganti S, Zhi J, Megyola C, Freeman AF et al. Signal transducer and activator of transcription 3 limits Epstein-Barr virus lytic activation in B lymphocytes. J Virol 2013; 87:11438–11446 [View Article][PubMed]
    [Google Scholar]
  38. Mccartney EM, Helbig KJ, Narayana SK, Eyre NS, Aloia AL et al. Signal transducer and activator of transcription 3 is a proviral host factor for hepatitis C virus. Hepatology 2013; 58:1558–1568 [View Article][PubMed]
    [Google Scholar]
  39. Mizutani T, Fukushi S, Murakami M, Hirano T, Saijo M et al. Tyrosine dephosphorylation of STAT3 in SARS coronavirus-infected Vero E6 cells. FEBS Lett 2004; 577:187–192 [View Article][PubMed]
    [Google Scholar]
  40. Sen N, Che X, Rajamani J, Zerboni L, Sung P et al. Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis. Proc Natl Acad Sci USA 2012; 109:600–605 [View Article][PubMed]
    [Google Scholar]
  41. Ulane CM, Rodriguez JJ, Parisien JP, Horvath CM. STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling. J Virol 2003; 77:6385–6393 [View Article][PubMed]
    [Google Scholar]
  42. Waris G, Huh KW, Siddiqui A. Mitochondrially associated hepatitis B virus X protein constitutively activates transcription factors STAT-3 and NF-kappa B via oxidative stress. Mol Cell Biol 2001; 21:7721–7730 [View Article][PubMed]
    [Google Scholar]
  43. Ponomarev ED, Veremeyko T, Barteneva N, Krichevsky AM, Weiner HL. MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α-PU.1 pathway. Nat Med 2011; 17:64–70 [View Article][PubMed]
    [Google Scholar]
  44. Xue Y, Ouyang K, Huang J, Zhou Y, Ouyang H et al. Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits. Cell 2013; 152:82–96 [View Article][PubMed]
    [Google Scholar]
  45. Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T et al. MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 2011; 476:228–231 [View Article][PubMed]
    [Google Scholar]
  46. Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W et al. Identification of tissue-specific microRNAs from mouse. Curr Biol 2002; 12:735–739 [View Article][PubMed]
    [Google Scholar]
  47. Du X, Wang H, Xu F, Huang Y, Liu Z et al. Enterovirus 71 induces apoptosis of SH‑SY5Y human neuroblastoma cells through stimulation of endogenous microRNA let-7b expression. Mol Med Rep 2015; 12:953–959 [View Article][PubMed]
    [Google Scholar]
  48. Ho BC, Yu IS, Lu LF, Rudensky A, Chen HY et al. Inhibition of miR-146a prevents enterovirus-induced death by restoring the production of type I interferon. Nat Commun 2014; 5:3344 [View Article][PubMed]
    [Google Scholar]
  49. Xu LJ, Jiang T, Zhao W, Han JF, Liu J et al. Parallel mRNA and microRNA profiling of HEV71-infected human neuroblastoma cells reveal the up-regulation of miR-1246 in association with DLG3 repression. PLoS One 2014; 9:e95272 [View Article][PubMed]
    [Google Scholar]
  50. Zheng Z, Ke X, Wang M, He S, Li Q et al. Human microRNA hsa-miR-296-5p suppresses enterovirus 71 replication by targeting the viral genome. J Virol 2013; 87:5645–5656 [View Article][PubMed]
    [Google Scholar]
  51. Fu Y, Xu W, Chen D, Feng C, Zhang L et al. Enterovirus 71 induces autophagy by regulating has-miR-30a expression to promote viral replication. Antiviral Res 2015; 124:43–53 [View Article][PubMed]
    [Google Scholar]
  52. Tang WF, Huang RT, Chien KY, Huang JY, Lau KS et al. host microrna mir-197 plays a negative regulatory role in the enterovirus 71 infectious cycle by targeting the ran protein. J Virol 2015; 90:1424–1438 [View Article][PubMed]
    [Google Scholar]
  53. Wen BP, Dai HJ, Yang YH, Zhuang Y, Sheng R. MicroRNA-23b inhibits enterovirus 71 replication through downregulation of EV71 VPl protein. Intervirology 2013; 56:195–200 [View Article][PubMed]
    [Google Scholar]
  54. Zhang L, Chen X, Shi Y, Zhou B, du C et al. miR-27a suppresses EV71 replication by directly targeting EGFR. Virus Genes 2014; 49:373–382 [View Article][PubMed]
    [Google Scholar]
  55. Xu C, He X, Zheng Z, Zhang Z, Wei C et al. Downregulation of microRNA miR-526a by enterovirus inhibits RIG-I-dependent innate immune response. J Virol 2014; 88:11356–11368 [View Article][PubMed]
    [Google Scholar]
  56. Chang YL, Ho BC, Sher S, Yu SL, Yang PC. miR-146a and miR-370 coordinate enterovirus 71-induced cell apoptosis through targeting SOS1 and GADD45β. Cell Microbiol 2015; 17:802–818 [View Article][PubMed]
    [Google Scholar]
  57. Lin TY, Hsia SH, Huang YC, Wu CT, Chang LY. Proinflammatory cytokine reactions in enterovirus 71 infections of the central nervous system. Clin Infect Dis 2003; 36:269–274 [View Article][PubMed]
    [Google Scholar]
  58. Chalaris A, Garbers C, Rabe B, Rose-John S, Scheller J. The soluble Interleukin 6 receptor: generation and role in inflammation and cancer. Eur J Cell Biol 2011; 90:484–494 [View Article][PubMed]
    [Google Scholar]
  59. Garbers C, Jänner N, Chalaris A, Moss ML, Floss DM et al. Species specificity of ADAM10 and ADAM17 proteins in interleukin-6 (IL-6) trans-signaling and novel role of ADAM10 in inducible IL-6 receptor shedding. J Biol Chem 2011; 286:14804–14811 [View Article][PubMed]
    [Google Scholar]
  60. Wang Q, Chen X, Feng J, Cao Y, Song Y et al. Soluble interleukin-6 receptor-mediated innate immune response to DNA and RNA viruses. J Virol 2013; 87:11244–11254 [View Article][PubMed]
    [Google Scholar]
  61. Yang X, Hao H, Xia Z, Xu G, Cao Z et al. Soluble IL-6 receptor and IL-27 Subunit p28 protein complex mediate the antiviral response through the type III IFN pathway. J Immunol 2016; 197:2369–2381 [View Article][PubMed]
    [Google Scholar]
  62. Yan XF, Gao S, Xia JF, Ye R, Yu H et al. Epidemic characteristics of hand, foot, and mouth disease in Shanghai from 2009 to 2010: Enterovirus 71 subgenotype C4 as the primary causative agent and a high incidence of mixed infections with coxsackievirus A16. Scand J Infect Dis 2012; 44:297–305 [View Article][PubMed]
    [Google Scholar]
  63. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA et al. Genome engineering using the CRISPR-Cas9 system. Nat Protoc 2013; 8:2281–2308 [View Article][PubMed]
    [Google Scholar]
  64. Sanjana NE, Shalem O, Zhang F. Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods 2014; 11:783–784 [View Article][PubMed]
    [Google Scholar]
  65. Wan G, Lim QE, Too HP. High-performance quantification of mature microRNAs by real-time RT-PCR using deoxyuridine-incorporated oligonucleotides and hemi-nested primers. RNA 2010; 16:1436–1445 [View Article][PubMed]
    [Google Scholar]
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