Human Cytomegalovirus miR-UL112-3p Targets TLR2 and Modulates the TLR2/IRAK1/NFκB Signaling Pathway

English version České info

Human cytomegalovirus (HCMV) is a herpesvirus that is a leading cause of congenital defects in newborns and can be deadly in people with weakened immunity. HCMV has developed multiple strategies to escape the host immune system. Among those, microRNAs (miRNAs) are short regulatory RNAs that target gene transcripts through sequence complementarity. HCMV expresses more than 20 miRNAs and several of them, in particular miR-UL112-3p, have been demonstrated to cooperate in evading the host antiviral immune response during infection. In this work we identified TLR2, a cell surface receptor that plays an important role in the detection and control of CMV infection, as a novel target of miR-UL112-3p. We demonstrate that miR-UL112-3p efficiently down-regulates endogenous TLR2 during infection, causing significant inhibition of the downstream signaling cascade. This work provides the first identified mechanism of TLR2 modulation by HCMV and is the first report of TLR2 targeting by a viral miRNA.

Vyšlo v časopise: Human Cytomegalovirus miR-UL112-3p Targets TLR2 and Modulates the TLR2/IRAK1/NFκB Signaling Pathway. PLoS Pathog 11(5): e32767. doi:10.1371/journal.ppat.1004881
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004881

Souhrn

Zdroje

1. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124: 783–801. 16497588

2. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11: 373–384. doi: 10.1038/ni.1863 20404851

3. Oliveira-Nascimento L, Massari P, Wetzler LM. The Role of TLR2 in Infection and Immunity. Front Immunol. 2012;3: 79. doi: 10.3389/fimmu.2012.00079 22566960

4. Ariza ME, Glaser R, Kaumaya PT, Jones C, Williams MV. The EBV-encoded dUTPase activates NF-kappa B through the TLR2 and MyD88-dependent signaling pathway. J Immunol. 2009;182: 851–859. 19124728

5. Chang S, Dolganiuc A, Szabo G. Toll-like receptors 1 and 6 are involved in TLR2-mediated macrophage activation by hepatitis C virus core and NS3 proteins. J Leukoc Biol. 2007;82: 479–487. 17595379

6. Compton T, Kurt-Jones EA, Boehme KW, Belko J, Latz E, Golenbock DT, et al. Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J Virol. 2003;77: 4588–4596. 12663765

7. Boehme KW, Guerrero M, Compton T. Human cytomegalovirus envelope glycoproteins B and H are necessary for TLR2 activation in permissive cells. J Immunol. 2006;177: 7094–7102. 17082626

8. Barbalat R, Lau L, Locksley RM, Barton GM. Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands. Nat Immunol. 2009;10: 1200–1207. doi: 10.1038/ni.1792 19801985

9. Kijpittayarit S, Eid AJ, Brown RA, Paya CV, Razonable RR. Relationship between Toll-like receptor 2 polymorphism and cytomegalovirus disease after liver transplantation. Clin Infect Dis. 2007;44: 1315–1320. 17443468

10. von Aulock S, Schroder NW, Traub S, Gueinzius K, Lorenz E, Hartung T, et al. Heterozygous toll-like receptor 2 polymorphism does not affect lipoteichoic acid-induced chemokine and inflammatory responses. Infect Immun. 2004;72: 1828–1831. 14977997

11. Hamann L, Gomma A, Schroder NW, Stamme C, Glaeser C, Schulz S, et al. A frequent toll-like receptor (TLR)-2 polymorphism is a risk factor for coronary restenosis. J Mol Med (Berl). 2005;83: 478–485. 15875151

12. Kang SH, Abdel-Massih RC, Brown RA, Dierkhising RA, Kremers WK, Razonable RR. Homozygosity for the toll-like receptor 2 R753Q single-nucleotide polymorphism is a risk factor for cytomegalovirus disease after liver transplantation. J Infect Dis. 2012;205: 639–646. doi: 10.1093/infdis/jir819 22219347

13. Xiong Y, Song C, Snyder GA, Sundberg EJ, Medvedev AE. R753Q polymorphism inhibits Toll-like receptor (TLR) 2 tyrosine phosphorylation, dimerization with TLR6, and recruitment of myeloid differentiation primary response protein 88. J Biol Chem. 2012;287: 38327–38337. doi: 10.1074/jbc.M112.375493 22992740

14. Szomolanyi-Tsuda E, Liang X, Welsh RM, Kurt-Jones EA, Finberg RW. Role for TLR2 in NK cell-mediated control of murine cytomegalovirus in vivo. J Virol. 2006;80: 4286–4291. 16611887

15. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136: 215–233. doi: 10.1016/j.cell.2009.01.002 19167326

16. Pfeffer S, Zavolan M, Grasser FA, Chien M, Russo JJ, Ju J, et al. Identification of virus-encoded microRNAs. Science. 2004;304: 734–736. 15118162

17. Grey F, Antoniewicz A, Allen E, Saugstad J, McShea A, Carrington JC, et al. Identification and characterization of human cytomegalovirus-encoded microRNAs. J Virol. 2005;79: 12095–12099. 16140786

18. Stark TJ, Arnold JD, Spector DH, Yeo GW. High-resolution profiling and analysis of viral and host small RNAs during human cytomegalovirus infection. J Virol. 2012;86: 226–235. doi: 10.1128/JVI.05903-11 22013051

19. Grey F. The role of microRNAs in herpesvirus latency and persistence. J Gen Virol. 2014.

20. Hook L, Hancock M, Landais I, Grabski R, Britt W, Nelson JA. Cytomegalovirus microRNAs. Curr Opin Virol. 2014;7: 40–46. doi: 10.1016/j.coviro.2014.03.015 24769092

21. Nachmani D, Stern-Ginossar N, Sarid R, Mandelboim O. Diverse herpesvirus microRNAs target the stress-induced immune ligand MICB to escape recognition by natural killer cells. Cell Host Microbe. 2009;5: 376–385. doi: 10.1016/j.chom.2009.03.003 19380116

22. Gottwein E, Corcoran DL, Mukherjee N, Skalsky RL, Hafner M, Nusbaum JD, et al. Viral microRNA targetome of KSHV-infected primary effusion lymphoma cell lines. Cell Host Microbe. 2011;10: 515–526. doi: 10.1016/j.chom.2011.09.012 22100165

23. Grey F, Meyers H, White EA, Spector DH, Nelson J. A human cytomegalovirus-encoded microRNA regulates expression of multiple viral genes involved in replication. PLoS Pathog. 2007;3: e163. 17983268

24. Umbach JL, Kramer MF, Jurak I, Karnowski HW, Coen DM, Cullen BR. MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature. 2008;454: 780–783. doi: 10.1038/nature07103 18596690

25. Tirabassi R, Hook L, Landais I, Grey F, Meyers H, Hewitt H, et al. Human cytomegalovirus US7 is regulated synergistically by two virally encoded microRNAs and by two distinct mechanisms. J Virol. 2011;85: 11938–11944. doi: 10.1128/JVI.05443-11 21900172

26. Samols MA, Skalsky RL, Maldonado AM, Riva A, Lopez MC, Baker HV, et al. Identification of cellular genes targeted by KSHV-encoded microRNAs. PLoS Pathog. 2007;3: e65. 17500590

27. Ziegelbauer JM, Sullivan CS, Ganem D. Tandem array-based expression screens identify host mRNA targets of virus-encoded microRNAs. Nat Genet. 2009;41: 130–134. doi: 10.1038/ng.266 19098914

28. Grey F, Tirabassi R, Meyers H, Wu G, McWeeney S, Hook L, et al. A viral microRNA down-regulates multiple cell cycle genes through mRNA 5'UTRs. PLoS Pathog. 2010;6: e1000967. doi: 10.1371/journal.ppat.1000967 20585629

29. Lei X, Bai Z, Ye F, Xie J, Kim CG, Huang Y, et al. Regulation of NF-kappaB inhibitor IkappaBalpha and viral replication by a KSHV microRNA. Nat Cell Biol. 2010;12: 193–199. doi: 10.1038/ncb2019 20081837

30. Lee SH, Kalejta RF, Kerry J, Semmes OJ, O'Connor CM, Khan Z, et al. BclAF1 restriction factor is neutralized by proteasomal degradation and microRNA repression during human cytomegalovirus infection. Proc Natl Acad Sci U S A. 2012;109: 9575–9580. doi: 10.1073/pnas.1207496109 22645331

31. Skalsky RL, Corcoran DL, Gottwein E, Frank CL, Kang D, Hafner M, et al. The viral and cellular microRNA targetome in lymphoblastoid cell lines. PLoS Pathog. 2012;8: e1002484. doi: 10.1371/journal.ppat.1002484 22291592

32. Hook LM, Grey F, Grabski R, Tirabassi R, Doyle T, Hancock M, et al. Cytomegalovirus miRNAs target secretory pathway genes to facilitate formation of the virion assembly compartment and reduce cytokine secretion. Cell Host Microbe. 2014;15: 363–373. doi: 10.1016/j.chom.2014.02.004 24629342

33. Kim Y, Lee S, Kim S, Kim D, Ahn JH, Ahn K. Human cytomegalovirus clinical strain-specific microRNA miR-UL148D targets the human chemokine RANTES during infection. PLoS Pathog. 2012;8: e1002577. doi: 10.1371/journal.ppat.1002577 22412377

34. Stern-Ginossar N, Elefant N, Zimmermann A, Wolf DG, Saleh N, Biton M, et al. Host immune system gene targeting by a viral miRNA. Science. 2007;317: 376–381. 17641203

35. Nachmani D, Lankry D, Wolf DG, Mandelboim O. The human cytomegalovirus microRNA miR-UL112 acts synergistically with a cellular microRNA to escape immune elimination. Nat Immunol. 2010;11: 806–813. doi: 10.1038/ni.1916 20694010

36. Abend JR, Ramalingam D, Kieffer-Kwon P, Uldrick TS, Yarchoan R, Ziegelbauer JM. Kaposi's sarcoma-associated herpesvirus microRNAs target IRAK1 and MYD88, two components of the toll-like receptor/interleukin-1R signaling cascade, to reduce inflammatory-cytokine expression. J Virol. 2012;86: 11663–11674. doi: 10.1128/JVI.01147-12 22896623

37. Chen Y, Chen J, Wang H, Shi J, Wu K, Liu S, et al. HCV-induced miR-21 contributes to evasion of host immune system by targeting MyD88 and IRAK1. PLoS Pathog. 2013;9: e1003248. doi: 10.1371/journal.ppat.1003248 23633945

38. Benakanakere MR, Li Q, Eskan MA, Singh AV, Zhao J, Galicia JC, et al. Modulation of TLR2 protein expression by miR-105 in human oral keratinocytes. J Biol Chem. 2009;284: 23107–23115. doi: 10.1074/jbc.M109.013862 19509287

39. Philippe L, Alsaleh G, Suffert G, Meyer A, Georgel P, Sibilia J, et al. TLR2 expression is regulated by microRNA miR-19 in rheumatoid fibroblast-like synoviocytes. J Immunol. 2012;188: 454–461. doi: 10.4049/jimmunol.1102348 22105995

40. Guo H, Chen Y, Hu X, Qian G, Ge S, Zhang J. The regulation of Toll-like receptor 2 by miR-143 suppresses the invasion and migration of a subset of human colorectal carcinoma cells. Mol Cancer. 2013;12: 77. doi: 10.1186/1476-4598-12-77 23866094

41. Sallustio F, Serino G, Costantino V, Curci C, Cox SN, De Palma G, et al. miR-1915 and miR-1225-5p regulate the expression of CD133, PAX2 and TLR2 in adult renal progenitor cells. PLoS One. 2013;8: e68296. doi: 10.1371/journal.pone.0068296 23861881

42. Xin C, Zhang H, Liu Z. miR-154 suppresses colorectal cancer cell growth and motility by targeting TLR2. Mol Cell Biochem. 2014;387: 271–277. doi: 10.1007/s11010-013-1892-3 24242044

43. Croft D, Mundo AF, Haw R, Milacic M, Weiser J, Wu G, et al. The Reactome pathway knowledgebase. Nucleic Acids Res. 2014;42: D472–477. doi: 10.1093/nar/gkt1102 24243840

44. Browne EP, Wing B, Coleman D, Shenk T. Altered cellular mRNA levels in human cytomegalovirus-infected fibroblasts: viral block to the accumulation of antiviral mRNAs. J Virol. 2001;75: 12319–12330. 11711622

45. Chan G, Guilbert LJ. Ultraviolet-inactivated human cytomegalovirus induces placental syncytiotrophoblast apoptosis in a Toll-like receptor-2 and tumour necrosis factor-alpha dependent manner. J Pathol. 2006;210: 111–120. 16826536

46. Lee RM, White MR, Hartshorn KL. Influenza a viruses upregulate neutrophil toll-like receptor 2 expression and function. Scand J Immunol. 2006;63: 81–89. 16476006

47. Villalba M, Hott M, Martin C, Aguila B, Valdivia S, Quezada C, et al. Herpes simplex virus type 1 induces simultaneous activation of Toll-like receptors 2 and 4 and expression of the endogenous ligand serum amyloid A in astrocytes. Med Microbiol Immunol. 2012;201: 371–379. doi: 10.1007/s00430-012-0247-0 22622619

48. Murphy E, Vanicek J, Robins H, Shenk T, Levine AJ. Suppression of immediate-early viral gene expression by herpesvirus-coded microRNAs: implications for latency. Proc Natl Acad Sci U S A. 2008;105: 5453–5458. doi: 10.1073/pnas.0711910105 18378902

49. Jarvis MA, Borton JA, Keech AM, Wong J, Britt WJ, Magun BE, et al. Human cytomegalovirus attenuates interleukin-1beta and tumor necrosis factor alpha proinflammatory signaling by inhibition of NF-kappaB activation. J Virol. 2006;80: 5588–5598. 16699040

50. Yew KH, Carpenter C, Duncan RS, Harrison CJ. Human cytomegalovirus induces TLR4 signaling components in monocytes altering TIRAP, TRAM and downstream interferon-beta and TNF-alpha expression. PLoS One. 2012;7: e44500. doi: 10.1371/journal.pone.0044500 22970235

51. Harwani SC, Lurain NS, Zariffard MR, Spear GT. Differential inhibition of human cytomegalovirus (HCMV) by toll-like receptor ligands mediated by interferon-beta in human foreskin fibroblasts and cervical tissue. Virol J. 2007;4: 133. 18053251

52. Wang JP, Kurt-Jones EA, Shin OS, Manchak MD, Levin MJ, Finberg RW. Varicella-zoster virus activates inflammatory cytokines in human monocytes and macrophages via Toll-like receptor 2. J Virol. 2005;79: 12658–12666. 16188968

53. Gutzeit C, Raftery MJ, Peiser M, Tischer KB, Ulrich M, Eberhardt M, et al. Identification of an important immunological difference between virulent varicella-zoster virus and its avirulent vaccine: viral disruption of dendritic cell instruction. J Immunol. 2010;185: 488–497. doi: 10.4049/jimmunol.0902817 20525895

54. Sen J, Liu X, Roller R, Knipe DM. Herpes simplex virus US3 tegument protein inhibits Toll-like receptor 2 signaling at or before TRAF6 ubiquitination. Virology. 2013;439: 65–73. doi: 10.1016/j.virol.2013.01.026 23478027

55. Durantel D, Zoulim F. Interplay between hepatitis B virus and TLR2-mediated innate immune responses: can restoration of TLR2 functions be a new therapeutic option? J Hepatol. 2012;57: 486–489. doi: 10.1016/j.jhep.2012.06.019 22728561

56. Wang S, Chen Z, Hu C, Qian F, Cheng Y, Wu M, et al. Hepatitis B virus surface antigen selectively inhibits TLR2 ligand-induced IL-12 production in monocytes/macrophages by interfering with JNK activation. J Immunol. 2013;190: 5142–5151. doi: 10.4049/jimmunol.1201625 23585678

57. Yao XD, Rosenthal KL. Herpes simplex virus type 2 virion host shutoff protein suppresses innate dsRNA antiviral pathways in human vaginal epithelial cells. J Gen Virol. 2011;92: 1981–1993. doi: 10.1099/vir.0.030296-0 21632561

58. Saetrom P, Heale BS, Snove O Jr., Aagaard L, Alluin J, Rossi JJ. Distance constraints between microRNA target sites dictate efficacy and cooperativity. Nucleic Acids Res. 2007;35: 2333–2342. 17389647

59. Brown RA, Gralewski JH, Razonable RR. The R753Q polymorphism abrogates toll-like receptor 2 signaling in response to human cytomegalovirus. Clin Infect Dis. 2009;49: e96–99. doi: 10.1086/644501 19814623

60. Leoni V, Gianni T, Salvioli S, Campadelli-Fiume G. Herpes simplex virus glycoproteins gH/gL and gB bind Toll-like receptor 2, and soluble gH/gL is sufficient to activate NF-kappaB. J Virol. 2012;86: 6555–6562. doi: 10.1128/JVI.00295-12 22496225

61. Aliprantis AO, Yang RB, Weiss DS, Godowski P, Zychlinsky A. The apoptotic signaling pathway activated by Toll-like receptor-2. EMBO J. 2000;19: 3325–3336. 10880445

62. Salaun B, Romero P, Lebecque S. Toll-like receptors' two-edged sword: when immunity meets apoptosis. Eur J Immunol. 2007;37: 3311–3318. 18034428

63. Aravalli RN, Hu S, Lokensgard JR. Toll-like receptor 2 signaling is a mediator of apoptosis in herpes simplex virus-infected microglia. J Neuroinflammation. 2007;4: 11. 17470292

64. Chan G, Hemmings DG, Yurochko AD, Guilbert LJ. Human cytomegalovirus-caused damage to placental trophoblasts mediated by immediate-early gene-induced tumor necrosis factor-alpha. Am J Pathol. 2002;161: 1371–1381. 12368210

65. Chaudhuri S, Lowen B, Chan G, Davey A, Riddell M, Guilbert LJ. Human cytomegalovirus interacts with toll-like receptor 2 and CD14 on syncytiotrophoblasts to stimulate expression of TNFalpha mRNA and apoptosis. Placenta. 2009;30: 994–1001. doi: 10.1016/j.placenta.2009.09.001 19796811

66. Goldmacher VS, Bartle LM, Skaletskaya A, Dionne CA, Kedersha NL, Vater CA, et al. A cytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated to Bcl-2. Proc Natl Acad Sci U S A. 1999;96: 12536–12541. 10535957

67. McCormick AL, Roback L, Livingston-Rosanoff D, St Clair C. The human cytomegalovirus UL36 gene controls caspase-dependent and-independent cell death programs activated by infection of monocytes differentiating to macrophages. J Virol. 2010;84: 5108–5123. doi: 10.1128/JVI.01345-09 20219915

68. Pegtel DM, van de Garde MD, Middeldorp JM. Viral miRNAs exploiting the endosomal-exosomal pathway for intercellular cross-talk and immune evasion. Biochim Biophys Acta. 2011;1809: 715–721. doi: 10.1016/j.bbagrm.2011.08.002 21855666

69. van der Grein SG, Nolte-'t Hoen EN. "Small Talk" in the Innate Immune System via RNA-Containing Extracellular Vesicles. Front Immunol. 2014;5: 542. doi: 10.3389/fimmu.2014.00542 25400635

70. Delorme-Axford E, Donker RB, Mouillet JF, Chu T, Bayer A, Ouyang Y, et al. Human placental trophoblasts confer viral resistance to recipient cells. Proc Natl Acad Sci U S A. 2013;110: 12048–12053. doi: 10.1073/pnas.1304718110 23818581

71. Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES, Lindenberg JL, et al. Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci U S A. 2010;107: 6328–6333. doi: 10.1073/pnas.0914843107 20304794

72. Li S, Zhu J, Zhang W, Chen Y, Zhang K, Popescu LM, et al. Signature microRNA expression profile of essential hypertension and its novel link to human cytomegalovirus infection. Circulation. 2011;124: 175–184. doi: 10.1161/CIRCULATIONAHA.110.012237 21690488

73. Sinzger C, Hahn G, Digel M, Katona R, Sampaio KL, Messerle M, et al. Cloning and sequencing of a highly productive, endotheliotropic virus strain derived from human cytomegalovirus TB40/E. J Gen Virol. 2008;89: 359–368. doi: 10.1099/vir.0.83286-0 18198366

74. DeFilippis VR, Robinson B, Keck TM, Hansen SG, Nelson JA, Fruh KJ. Interferon regulatory factor 3 is necessary for induction of antiviral genes during human cytomegalovirus infection. J Virol. 2006;80: 1032–1037. 16379004

75. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9: 671–675. 22930834