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RSV-Induced H3K4 Demethylase KDM5B Leads to Regulation of Dendritic Cell-Derived Innate Cytokines and Exacerbates Pathogenesis


Respiratory syncytial virus (RSV) is a significant public health concern. Nearly all children are infected by two years of age, and severe infection often results in hospitalization. There is no vaccine for RSV, and previous attempts have resulted in increased disease severity in immunized children once they were exposed to the virus. Therefore, a better understanding of how RSV directs the immune response is needed. In this study, we found that the protein KDM5B regulates an epigenetic mechanism that directs the immune response to RSV. KDM5B suppressed the activation of key antiviral signals in dendritic cells, and inhibition of KDM5B led to gene activation and increased antiviral function. This correlated with decreased pathology in the lungs. Therefore, our data suggest that new attempts at designing a vaccine should consider the effects of vaccination on dendritic cells, and should consider strategies that will increase antiviral signals from dendritic cells.


Vyšlo v časopise: RSV-Induced H3K4 Demethylase KDM5B Leads to Regulation of Dendritic Cell-Derived Innate Cytokines and Exacerbates Pathogenesis. PLoS Pathog 11(6): e32767. doi:10.1371/journal.ppat.1004978
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004978

Souhrn

Respiratory syncytial virus (RSV) is a significant public health concern. Nearly all children are infected by two years of age, and severe infection often results in hospitalization. There is no vaccine for RSV, and previous attempts have resulted in increased disease severity in immunized children once they were exposed to the virus. Therefore, a better understanding of how RSV directs the immune response is needed. In this study, we found that the protein KDM5B regulates an epigenetic mechanism that directs the immune response to RSV. KDM5B suppressed the activation of key antiviral signals in dendritic cells, and inhibition of KDM5B led to gene activation and increased antiviral function. This correlated with decreased pathology in the lungs. Therefore, our data suggest that new attempts at designing a vaccine should consider the effects of vaccination on dendritic cells, and should consider strategies that will increase antiviral signals from dendritic cells.


Zdroje

1. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, et al. Bronchiolitis-associated hospitalizations among US children, 1980–1996. JAMA 1999;282: 1440–1446. 10535434

2. Simoes EA. Immunoprophylaxis of respiratory syncytial virus: global experience. Respir Res 2002;3 Suppl 1: S26–33. 12119055

3. Shay DK, Holman RC, Roosevelt GE, Clarke MJ, Anderson LJ. Bronchiolitis-associated mortality and estimates of respiratory syncytial virus-associated deaths among US children, 1979–1997. J Infect Dis 2001;183: 16–22. 11076709

4. Howard TS, Hoffman LH, Stang PE, Simoes EA. Respiratory syncytial virus pneumonia in the hospital setting: length of stay, charges, and mortality. J Pediatr 2000;137: 227–232. 10931416

5. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med 2000;161: 1501–1507. 10806145

6. Sigurs N, Gustafsson PM, Bjarnason R, Lundberg F, Schmidt S, et al. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. Am J Respir Crit Care Med 2005;171: 137–141. 15516534

7. Hall CB, Walsh EE, Long CE, Schnabel KC. Immunity to and frequency of reinfection with respiratory syncytial virus. J Infect Dis 1991;163: 693–698. 2010624

8. Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol 1969;89: 422–434. 4305198

9. Ling Z, Tran KC, Teng MN. Human respiratory syncytial virus nonstructural protein NS2 antagonizes the activation of beta interferon transcription by interacting with RIG-I. J Virol 2009;83: 3734–3742. doi: 10.1128/JVI.02434-08 19193793

10. Spann KM, Tran KC, Collins PL. Effects of nonstructural proteins NS1 and NS2 of human respiratory syncytial virus on interferon regulatory factor 3, NF-kappaB, and proinflammatory cytokines. J Virol 2005;79: 5353–5362. 15827150

11. Rudd BD, Smit JJ, Flavell RA, Alexopoulou L, Schaller MA, et al. Deletion of TLR3 alters the pulmonary immune environment and mucus production during respiratory syncytial virus infection. J Immunol 2006;176: 1937–1942. 16424225

12. Koch CM, Andrews RM, Flicek P, Dillon SC, Karaoz U, et al. The landscape of histone modifications across 1% of the human genome in five human cell lines. Genome Res 2007;17: 691–707. 17567990

13. Pekowska A, Benoukraf T, Zacarias-Cabeza J, Belhocine M, Koch F, et al. H3K4 tri-methylation provides an epigenetic signature of active enhancers. EMBO J 2011;30: 4198–4210. doi: 10.1038/emboj.2011.295 21847099

14. Riising EM, Comet I, Leblanc B, Wu X, Johansen JV, et al. Gene silencing triggers polycomb repressive complex 2 recruitment to CpG islands genome wide. Mol Cell 2014;55: 347–360. doi: 10.1016/j.molcel.2014.06.005 24999238

15. Lee GR, Kim ST, Spilianakis CG, Fields PE, Flavell RA. T helper cell differentiation: regulation by cis elements and epigenetics. Immunity 2006;24: 369–379. 16618596

16. Wei G, Wei L, Zhu J, Zang C, Hu-Li J, et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 2009;30: 155–167. doi: 10.1016/j.immuni.2008.12.009 19144320

17. Wen H, Dou Y, Hogaboam CM, Kunkel SL. Epigenetic regulation of dendritic cell-derived interleukin-12 facilitates immunosuppression after a severe innate immune response. Blood 2008;111: 1797–1804. 18055863

18. Roesch A, Mueller AM, Stempfl T, Moehle C, Landthaler M, et al. RBP2-H1/JARID1B is a transcriptional regulator with a tumor suppressive potential in melanoma cells. Int J Cancer 2008;122: 1047–1057. 17973255

19. Catteau A, Rosewell I, Solomon E, Taylor-Papadimitriou J. A short region of the promoter of the breast cancer associated PLU-1 gene can regulate transcription in vitro and in vivo. Int J Oncol 2004;25: 5–16. 15201984

20. Madsen B, Tarsounas M, Burchell JM, Hall D, Poulsom R, et al. PLU-1, a transcriptional repressor and putative testis-cancer antigen, has a specific expression and localisation pattern during meiosis. Chromosoma 2003;112: 124–132. 14579128

21. Shin HM, Kapoor VN, Guan T, Kaech SM, Welsh RM, et al. Epigenetic modifications induced by Blimp-1 Regulate CD8(+) T cell memory progression during acute virus infection. Immunity 2013;39: 661–675. doi: 10.1016/j.immuni.2013.08.032 24120360

22. Lukacs NW, Smit JJ, Mukherjee S, Morris SB, Nunez G, et al. Respiratory virus-induced TLR7 activation controls IL-17-associated increased mucus via IL-23 regulation. J Immunol 2010;185: 2231–2239. doi: 10.4049/jimmunol.1000733 20624950

23. Rudd BD, Burstein E, Duckett CS, Li X, Lukacs NW. Differential role for TLR3 in respiratory syncytial virus-induced chemokine expression. J Virol 2005;79: 3350–3357. 15731229

24. Kristensen LH, Nielsen AL, Helgstrand C, Lees M, Cloos P, et al. Studies of H3K4me3 demethylation by KDM5B/Jarid1B/PLU1 reveals strong substrate recognition in vitro and identifies 2,4-pyridine-dicarboxylic acid as an in vitro and in cell inhibitor. FEBS J 2012;279: 1905–1914. doi: 10.1111/j.1742-4658.2012.08567.x 22420752

25. Sayegh J, Cao J, Zou MR, Morales A, Blair LP, et al. Identification of small molecule inhibitors of Jumonji AT-rich interactive domain 1B (JARID1B) histone demethylase by a sensitive high throughput screen. J Biol Chem 2013;288: 9408–9417. doi: 10.1074/jbc.M112.419861 23408432

26. Durbin JE, Johnson TR, Durbin RK, Mertz SE, Morotti RA, et al. The role of IFN in respiratory syncytial virus pathogenesis. J Immunol 2002;168: 2944–2952. 11884466

27. Reed M, Morris SH, Jang S, Mukherjee S, Yue Z, et al. Autophagy-inducing protein beclin-1 in dendritic cells regulates CD4 T cell responses and disease severity during respiratory syncytial virus infection. J Immunol 2013;191: 2526–2537. doi: 10.4049/jimmunol.1300477 23894198

28. Jang S, Smit J, Kallal LE, Lukacs NW. Respiratory syncytial virus infection modifies and accelerates pulmonary disease via DC activation and migration. J Leukoc Biol 2013;94: 5–15. doi: 10.1189/jlb.0412195 23293372

29. GeurtsvanKessel CH, Lambrecht BN. Division of labor between dendritic cell subsets of the lung. Mucosal Immunol 2008;1: 442–450. doi: 10.1038/mi.2008.39 19079211

30. Sung SS, Fu SM, Rose CE Jr., Gaskin F, Ju ST, et al. A major lung CD103 (alphaE)-beta7 integrin-positive epithelial dendritic cell population expressing Langerin and tight junction proteins. J Immunol 2006;176: 2161–2172. 16455972

31. Albert M, Schmitz SU, Kooistra SM, Malatesta M, Morales Torres C, et al. The histone demethylase Jarid1b ensures faithful mouse development by protecting developmental genes from aberrant H3K4me3. PLoS Genet 2013;9: e1003461. doi: 10.1371/journal.pgen.1003461 23637629

32. Stokes KL, Chi MH, Sakamoto K, Newcomb DC, Currier MG, et al. Differential pathogenesis of respiratory syncytial virus clinical isolates in BALB/c mice. J Virol 2011;85: 5782–5793. doi: 10.1128/JVI.01693-10 21471228

33. Suarez-Alvarez B, Rodriguez RM, Fraga MF, Lopez-Larrea C. DNA methylation: a promising landscape for immune system-related diseases. Trends Genet 2012;28: 506–514. doi: 10.1016/j.tig.2012.06.005 22824525

34. Rodriguez-Cortez VC, Hernando H, de la Rica L, Vento R, Ballestar E. Epigenomic deregulation in the immune system. Epigenomics 2011;3: 697–713. doi: 10.2217/epi.11.99 22126290

35. Adhya D, Basu A. Epigenetic modulation of host: new insights into immune evasion by viruses. J Biosci 2010;35: 647–663. 21289446

36. Groskreutz DJ, Monick MM, Powers LS, Yarovinsky TO, Look DC, et al. Respiratory syncytial virus induces TLR3 protein and protein kinase R, leading to increased double-stranded RNA responsiveness in airway epithelial cells. J Immunol 2006;176: 1733–1740. 16424203

37. van der Sluijs KF, van Elden LJ, Nijhuis M, Schuurman R, Pater JM, et al. IL-10 is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection. J Immunol 2004;172: 7603–7609. 15187140

38. Colamussi ML, White MR, Crouch E, Hartshorn KL. Influenza A virus accelerates neutrophil apoptosis and markedly potentiates apoptotic effects of bacteria. Blood 1999;93: 2395–2403. 10090951

39. Walzl G, Tafuro S, Moss P, Openshaw PJ, Hussell T. Influenza virus lung infection protects from respiratory syncytial virus-induced immunopathology. J Exp Med 2000;192: 1317–1326. 11067880

40. Kristjansson S, Bjarnarson SP, Wennergren G, Palsdottir AH, Arnadottir T, et al. Respiratory syncytial virus and other respiratory viruses during the first 3 months of life promote a local TH2-like response. J Allergy Clin Immunol 2005;116: 805–811. 16210054

41. Legg JP, Hussain IR, Warner JA, Johnston SL, Warner JO. Type 1 and type 2 cytokine imbalance in acute respiratory syncytial virus bronchiolitis. Am J Respir Crit Care Med 2003;168: 633–639. 12773328

42. Siegrist CA. Neonatal and early life vaccinology. Vaccine 2001;19: 3331–3346. 11348697

43. Jie Z, Dinwiddie DL, Senft AP, Harrod KS. Regulation of STAT signaling in mouse bone marrow derived dendritic cells by respiratory syncytial virus. Virus Res 2011;156: 127–133. doi: 10.1016/j.virusres.2011.01.007 21255624

44. Shingai M, Azuma M, Ebihara T, Sasai M, Funami K, et al. Soluble G protein of respiratory syncytial virus inhibits Toll-like receptor 3/4-mediated IFN-beta induction. Int Immunol 2008;20: 1169–1180. doi: 10.1093/intimm/dxn074 18611945

45. Jewell NA, Vaghefi N, Mertz SE, Akter P, Peebles RS Jr., et al. Differential type I interferon induction by respiratory syncytial virus and influenza a virus in vivo. J Virol 2007;81: 9790–9800. 17626092

46. Guerrero-Plata A, Kolli D, Hong C, Casola A, Garofalo RP. Subversion of pulmonary dendritic cell function by paramyxovirus infections. J Immunol 2009;182: 3072–3083. doi: 10.4049/jimmunol.0802262 19234204

47. Ramaswamy M, Shi L, Monick MM, Hunninghake GW, Look DC. Specific inhibition of type I interferon signal transduction by respiratory syncytial virus. Am J Respir Cell Mol Biol 2004;30: 893–900. 14722224

48. Rudd BD, Luker GD, Luker KE, Peebles RS, Lukacs NW. Type I interferon regulates respiratory virus infected dendritic cell maturation and cytokine production. Viral Immunol 2007;20: 531–540. 18158727

49. Hashimoto K, Durbin JE, Zhou W, Collins RD, Ho SB, et al. Respiratory syncytial virus infection in the absence of STAT 1 results in airway dysfunction, airway mucus, and augmented IL-17 levels. J Allergy Clin Immunol 2005;116: 550–557. 16159623

50. Nagai T, Devergne O, Mueller TF, Perkins DL, van Seventer JM, et al. Timing of IFN-beta exposure during human dendritic cell maturation and naive Th cell stimulation has contrasting effects on Th1 subset generation: a role for IFN-beta-mediated regulation of IL-12 family cytokines and IL-18 in naive Th cell differentiation. J Immunol 2003;171: 5233–5243. 14607924

51. Henig N, Avidan N, Mandel I, Staun-Ram E, Ginzburg E, et al. Interferon-beta induces distinct gene expression response patterns in human monocytes versus T cells. PLoS One 2013;8: e62366. doi: 10.1371/journal.pone.0062366 23626809

52. Boyapalle S, Wong T, Garay J, Teng M, San Juan-Vergara H, et al. Respiratory syncytial virus NS1 protein colocalizes with mitochondrial antiviral signaling protein MAVS following infection. PLoS One 2012;7: e29386. doi: 10.1371/journal.pone.0029386 22383950

53. Munir S, Hillyer P, Le Nouen C, Buchholz UJ, Rabin RL, et al. Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response. PLoS Pathog 2011;7: e1001336. doi: 10.1371/journal.ppat.1001336 21533073

54. Munir S, Le Nouen C, Luongo C, Buchholz UJ, Collins PL, et al. Nonstructural proteins 1 and 2 of respiratory syncytial virus suppress maturation of human dendritic cells. J Virol 2008;82: 8780–8796. doi: 10.1128/JVI.00630-08 18562519

55. Moore EC, Barber J, Tripp RA. Respiratory syncytial virus (RSV) attachment and nonstructural proteins modify the type I interferon response associated with suppressor of cytokine signaling (SOCS) proteins and IFN-stimulated gene-15 (ISG15). Virol J 2008;5: 116. doi: 10.1186/1743-422X-5-116 18851747

56. Spann KM, Tran KC, Chi B, Rabin RL, Collins PL. Suppression of the induction of alpha, beta, and lambda interferons by the NS1 and NS2 proteins of human respiratory syncytial virus in human epithelial cells and macrophages [corrected]. J Virol 2004;78: 4363–4369. 15047850

57. Teng MN, Whitehead SS, Bermingham A, St Claire M, Elkins WR, et al. Recombinant respiratory syncytial virus that does not express the NS1 or M2-2 protein is highly attenuated and immunogenic in chimpanzees. J Virol 2000;74: 9317–9321. 10982380

58. Brogdon JL, Xu Y, Szabo SJ, An S, Buxton F, et al. Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function. Blood 2007;109: 1123–1130. 17008546

59. Fang TC, Schaefer U, Mecklenbrauker I, Stienen A, Dewell S, et al. Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response. J Exp Med 2012;209: 661–669. doi: 10.1084/jem.20112343 22412156

60. Schmitz SU, Albert M, Malatesta M, Morey L, Johansen JV, et al. Jarid1b targets genes regulating development and is involved in neural differentiation. Embo J 2011;30: 4586–4600. doi: 10.1038/emboj.2011.383 22020125

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