The Epigenetic Regulator G9a Mediates Tolerance to RNA Virus Infection in


Multicellular organisms deploy various strategies to fight microbial infections. Invading pathogens may be eradicated directly by antimicrobial effectors of the immune system. Another strategy consists of increasing the tolerance of the host to infection, for example, by limiting the adverse effects of the immune response. The molecular mechanisms underlying this novel concept remain largely uncharacterized. Here, we demonstrate that the epigenetic regulator G9a mediates tolerance to virus infection in Drosophila. We found that G9a-deficient flies succumb faster than control flies to infection with RNA viruses, but that the viral burden did not significantly differ. Unexpectedly, mutant flies express higher levels of genes that are regulated by the Jak-Stat signaling pathway, which in other studies was found to be important for antiviral defense. Exploiting the genetic toolbox in Drosophila, we demonstrate that Jak-Stat hyperactivation induces early mortality after virus infection. Precise control of immune pathways is essential to ensure efficient immunity, while preventing damage due to excessive immune responses. Our results indicate that G9a, an epigenetic modifier, dampens Jak-Stat responses to prevent immunopathology. Therefore, we propose epigenetic regulation of immunity as a new paradigm for disease tolerance.


Vyšlo v časopise: The Epigenetic Regulator G9a Mediates Tolerance to RNA Virus Infection in. PLoS Pathog 11(4): e32767. doi:10.1371/journal.ppat.1004692
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1004692

Souhrn

Multicellular organisms deploy various strategies to fight microbial infections. Invading pathogens may be eradicated directly by antimicrobial effectors of the immune system. Another strategy consists of increasing the tolerance of the host to infection, for example, by limiting the adverse effects of the immune response. The molecular mechanisms underlying this novel concept remain largely uncharacterized. Here, we demonstrate that the epigenetic regulator G9a mediates tolerance to virus infection in Drosophila. We found that G9a-deficient flies succumb faster than control flies to infection with RNA viruses, but that the viral burden did not significantly differ. Unexpectedly, mutant flies express higher levels of genes that are regulated by the Jak-Stat signaling pathway, which in other studies was found to be important for antiviral defense. Exploiting the genetic toolbox in Drosophila, we demonstrate that Jak-Stat hyperactivation induces early mortality after virus infection. Precise control of immune pathways is essential to ensure efficient immunity, while preventing damage due to excessive immune responses. Our results indicate that G9a, an epigenetic modifier, dampens Jak-Stat responses to prevent immunopathology. Therefore, we propose epigenetic regulation of immunity as a new paradigm for disease tolerance.


Zdroje

1. Schneider DS (2007) How and Why Does a Fly Turn Its Immune System Off? PLoS Biol 5: e247. 17880266

2. Han J, Ulevitch RJ (2005) Limiting inflammatory responses during activation of innate immunity. Nat Immunol 6: 1198–1205. 16369559

3. Medzhitov R, Schneider DS, Soares MP (2012) Disease Tolerance as a Defense Strategy. Science 335: 936–941. doi: 10.1126/science.1214935 22363001

4. Ayres JS, Schneider DS (2012) Tolerance of infections. Annu Rev Immunol 30: 271–294. doi: 10.1146/annurev-immunol-020711-075030 22224770

5. Lemaitre B, Hoffmann J (2007) The host defense of Drosophila melanogaster. Annu Rev Immunol 25: 697–743. 17201680

6. van Mierlo JT, van Cleef KW, van Rij RP (2011) Defense and counterdefense in the RNAi-based antiviral immune system in insects. Methods Mol Biol 721: 3–22. doi: 10.1007/978-1-61779-037-9_1 21431676

7. Kemp C, Mueller S, Goto A, Barbier V, Paro S, et al. (2013) Broad RNA interference-mediated antiviral immunity and virus-specific inducible responses in Drosophila. J Immunol 190: 650–658. doi: 10.4049/jimmunol.1102486 23255357

8. Dostert C, Jouanguy E, Irving P, Troxler L, Galiana-Arnoux D, et al. (2005) The Jak-STAT signaling pathway is required but not sufficient for the antiviral response of drosophila. Nat Immunol 6: 946–953. 16086017

9. Rawlings JS, Rosler KM, Harrison DA (2004) The JAK/STAT signaling pathway. J Cell Sci 117: 1281–1283. 15020666

10. Zeidler MP, Bach EA, Perrimon N (2000) The roles of the Drosophila JAK/STAT pathway. Oncogene 19: 2598–2606. 10851058

11. Dupuis S, Jouanguy E, Al-Hajjar S, Fieschi C, Al-Mohsen IZ, et al. (2003) Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet 33: 388–391. 12590259

12. van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LA, et al. (2011) STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med 365: 54–61. doi: 10.1056/NEJMoa1100102 21714643

13. O'Shea JJ, Holland SM, Staudt LM (2013) JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 368: 161–170. doi: 10.1056/NEJMra1202117 23301733

14. Theofilopoulos AN, Baccala R, Beutler B, Kono DH (2005) Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol 23: 307–336. 15771573

15. Merkling SH, van Rij RP (2013) Beyond RNAi: antiviral defense strategies in Drosophila and mosquito. J Insect Physiol 59: 159–170. doi: 10.1016/j.jinsphys.2012.07.004 22824741

16. Arbouzova NI, Zeidler MP (2006) JAK/STAT signalling in Drosophila: insights into conserved regulatory and cellular functions. Development 133: 2605–2616. 16794031

17. Stabell M, Eskeland R, Bjorkmo M, Larsson J, Aalen RB, et al. (2006) The Drosophila G9a gene encodes a multi-catalytic histone methyltransferase required for normal development. Nucleic Acids Res 34: 4609–4621. 16963494

18. Schaefer A, Sampath SC, Intrator A, Min A, Gertler TS, et al. (2009) Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron 64: 678–691. doi: 10.1016/j.neuron.2009.11.019 20005824

19. Brower-Toland B, Riddle NC, Jiang H, Huisinga KL, Elgin SC (2009) Multiple SET methyltransferases are required to maintain normal heterochromatin domains in the genome of Drosophila melanogaster. Genetics 181: 1303–1319. doi: 10.1534/genetics.108.100271 19189944

20. Kramer JM, Kochinke K, Oortveld MA, Marks H, Kramer D, et al. (2011) Epigenetic regulation of learning and memory by Drosophila EHMT/G9a. PLoS Biol 9: e1000569. doi: 10.1371/journal.pbio.1000569 21245904

21. Vakoc CR, Mandat SA, Olenchock BA, Blobel GA (2005) Histone H3 lysine 9 methylation and HP1gamma are associated with transcription elongation through mammalian chromatin. Mol Cell 19: 381–391. 16061184

22. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, et al. (2007) High-resolution profiling of histone methylations in the human genome. Cell 129: 823–837. 17512414

23. Seum C, Bontron S, Reo E, Delattre M, Spierer P (2007) Drosophila G9a is a nonessential gene. Genetics 177: 1955–1957. 18039887

24. Bronkhorst AW, van Cleef KW, Vodovar N, Ince IA, Blanc H, et al. (2012) The DNA virus Invertebrate iridescent virus 6 is a target of the Drosophila RNAi machinery. Proc Natl Acad Sci U S A 109: E3604–3613. doi: 10.1073/pnas.1207213109 23151511

25. Deddouche S, Matt N, Budd A, Mueller S, Kemp C, et al. (2008) The DExD/H-box helicase Dicer-2 mediates the induction of antiviral activity in drosophila. Nat Immunol 9: 1425–1432. doi: 10.1038/ni.1664 18953338

26. Meyer WJ, Schreiber S, Guo Y, Volkmann T, Welte MA, et al. (2006) Overlapping functions of argonaute proteins in patterning and morphogenesis of Drosophila embryos. PLoS Genet 2: e134. 16934003

27. van Mierlo JT, Bronkhorst AW, Overheul GJ, Sadanandan SA, Ekstrom JO, et al. (2012) Convergent evolution of argonaute-2 slicer antagonism in two distinct insect RNA viruses. PLoS Pathog 8: e1002872. doi: 10.1371/journal.ppat.1002872 22916019

28. van Cleef KW, van Mierlo JT, van den Beek M, van Rij RP (2011) Identification of viral suppressors of RNAi by a reporter assay in Drosophila S2 cell culture. Methods Mol Biol 721: 201–213. doi: 10.1007/978-1-61779-037-9_12 21431687

29. Ferreira ÁG, Naylor H, Esteves SS, Pais IS, Martins NE, et al. (2014) The Toll-Dorsal Pathway Is Required for Resistance to Viral Oral Infection in Drosophila. PLoS Pathog 10: e1004507. doi: 10.1371/journal.ppat.1004507 25473839

30. Zambon Ra, Nandakumar M, Vakharia VN, Wu LP (2005) The Toll pathway is important for an antiviral response in Drosophila. Proceedings of the National Academy of Sciences of the United States of America 102: 7257–7262. 15878994

31. Avadhanula V, Weasner BP, Hardy GG, Kumar JP, Hardy RW (2009) A novel system for the launch of alphavirus RNA synthesis reveals a role for the Imd pathway in arthropod antiviral response. PLoS Pathog 5: e1000582. doi: 10.1371/journal.ppat.1000582 19763182

32. Coste F, Kemp C, Bobezeau V, Hetru C, Kellenberger C, et al. (2012) Crystal structure of Diedel, a marker of the immune response of Drosophila melanogaster. PLoS One 7: e33416. doi: 10.1371/journal.pone.0033416 22442689

33. Zambelli F, Pesole G, Pavesi G (2009) Pscan: finding over-represented transcription factor binding site motifs in sequences from co-regulated or co-expressed genes. Nucleic Acids Res 37: W247–252. doi: 10.1093/nar/gkp464 19487240

34. Bina S, Wright VM, Fisher KH, Milo M, Zeidler MP (2010) Transcriptional targets of Drosophila JAK/STAT pathway signalling as effectors of haematopoietic tumour formation. EMBO Rep 11: 201–207. doi: 10.1038/embor.2010.1 20168330

35. Karsten P, Hader S, Zeidler MP (2002) Cloning and expression of Drosophila SOCS36E and its potential regulation by the JAK/STAT pathway. Mech Dev 117: 343–346. 12204282

36. Rivas ML, Cobreros L, Zeidler MP, Hombria JC (2008) Plasticity of Drosophila Stat DNA binding shows an evolutionary basis for Stat transcription factor preferences. EMBO Rep 9: 1114–1120. doi: 10.1038/embor.2008.170 18802449

37. Agaisse H, Perrimon N (2004) The roles of JAK/STAT signaling in Drosophila immune responses. Immunol Rev 198: 72–82. 15199955

38. Hombria JC, Brown S (2002) The fertile field of Drosophila Jak/STAT signalling. Curr Biol 12: R569–575. 12194841

39. Brown S, Hu N, Hombria JC (2001) Identification of the first invertebrate interleukin JAK/STAT receptor, the Drosophila gene domeless. Curr Biol 11: 1700–1705. 11696329

40. Croker BA, Kiu H, Nicholson SE (2008) SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol 19: 414–422. doi: 10.1016/j.semcdb.2008.07.010 18708154

41. McGuire SE, Roman G, Davis RL (2004) Gene expression systems in Drosophila: a synthesis of time and space. Trends Genet 20: 384–391. 15262411

42. Ferrandon D (2013) The complementary facets of epithelial host defenses in the genetic model organism Drosophila melanogaster: from resistance to resilience. Curr Opin Immunol 25: 59–70. doi: 10.1016/j.coi.2012.11.008 23228366

43. Ayres JS, Schneider DS (2009) The role of anorexia in resistance and tolerance to infections in Drosophila. PLoS biology 7: e1000150–e1000150. doi: 10.1371/journal.pbio.1000150 19597539

44. Ayres JS, Freitag N, Schneider DS (2008) Identification of Drosophila mutants altering defense of and endurance to Listeria monocytogenes infection. Genetics 178: 1807–1815. doi: 10.1534/genetics.107.083782 18245331

45. Ayres JS, Schneider DS (2008) A signaling protease required for melanization in Drosophila affects resistance and tolerance of infections. PLoS biology 6: 2764–2773. doi: 10.1371/journal.pbio.0060305 19071960

46. Teixeira L, Ferreira A, Ashburner M (2008) The bacterial symbiont Wolbachia induces resistance to RNA viral infections in Drosophila melanogaster. PLoS Biol 6: e2. doi: 10.1371/journal.pbio.1000002 19222304

47. Osborne SE, Leong YS, O'Neill SL, Johnson KN (2009) Variation in antiviral protection mediated by different Wolbachia strains in Drosophila simulans. PLoS pathogens 5: e1000656–e1000656. doi: 10.1371/journal.ppat.1000656 19911047

48. Taillebourg E, Schneider DS, Fauvarque MO (2014) The Drosophila deubiquitinating enzyme dUSP36 acts in the hemocytes for tolerance to Listeria monocytogenes infections. J Innate Immun 6: 632–638. doi: 10.1159/000360293 24777180

49. Ryu JH, Kim SH, Lee HY, Bai JY, Nam YD, et al. (2008) Innate immune homeostasis by the homeobox gene caudal and commensal-gut mutualism in Drosophila. Science 319: 777–782. doi: 10.1126/science.1149357 18218863

50. Gordon MD, Dionne MS, Schneider DS, Nusse R (2005) WntD is a feedback inhibitor of Dorsal/NF-kappaB in Drosophila development and immunity. Nature 437: 746–749. 16107793

51. Paredes JC, Welchman DP, Poidevin M, Lemaitre B (2011) Negative regulation by amidase PGRPs shapes the Drosophila antibacterial response and protects the fly from innocuous infection. Immunity 35: 770–779. doi: 10.1016/j.immuni.2011.09.018 22118526

52. Kim LK, Choi UY, Cho HS, Lee JS, Lee WB, et al. (2007) Down-regulation of NF-kappaB target genes by the AP-1 and STAT complex during the innate immune response in Drosophila. PLoS Biol 5: e238. 17803358

53. Kim T, Yoon J, Cho H, Lee WB, Kim J, et al. (2005) Downregulation of lipopolysaccharide response in Drosophila by negative crosstalk between the AP1 and NF-kappaB signaling modules. Nat Immunol 6: 211–218. 15640802

54. Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, et al. (2002) G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev 16: 1779–1791. 12130538

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

56. Willemsen MH, Vulto-van Silfhout AT, Nillesen WM, Wissink-Lindhout WM, van Bokhoven H, et al. (2012) Update on Kleefstra Syndrome. Mol Syndromol 2: 202–212. 22670141

57. Hrdlicka L, Gibson M, Kiger A, Micchelli C, Schober M, et al. (2002) Analysis of twenty-four Gal4 lines in Drosophila melanogaster. Genesis 34: 51–57. 12324947

58. Goto A, Kadowaki T, Kitagawa Y (2003) Drosophila hemolectin gene is expressed in embryonic and larval hemocytes and its knock down causes bleeding defects. Developmental Biology 264: 582–591. 14651939

59. Bach EA, Vincent S, Zeidler MP, Perrimon N (2003) A sensitized genetic screen to identify novel regulators and components of the Drosophila janus kinase/signal transducer and activator of transcription pathway. Genetics 165: 1149–1166. 14668372

60. McGuire SE, Le PT, Osborn AJ, Matsumoto K, Davis RL (2003) Spatiotemporal rescue of memory dysfunction in Drosophila. Science 302: 1765–1768. 14657498

61. Okamura K, Ishizuka A, Siomi H, Siomi MC (2004) Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways. Genes Dev 18: 1655–1666. 15231716

62. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann Ja (1996) The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86: 973–983. 8808632

63. Reed LJ, Muench H (1938) A simple method of estimating fifty per cent endpoints Am J Epidemiol 27: 493–497.

64. Isoe J, Kunz S, Manhart C, Wells MA, Miesfeld RL (2007) Regulated expression of microinjected DNA in adult Aedes aegypti mosquitoes. Insect Mol Biol 16: 83–92. 17257211

65. Colpitts TM, Cox J, Vanlandingham DL, Feitosa FM, Cheng G, et al. (2011) Alterations in the Aedes aegypti transcriptome during infection with West Nile, dengue and yellow fever viruses. PLoS Pathog 7: e1002189. doi: 10.1371/journal.ppat.1002189 21909258

66. Yasuhara JC, Wakimoto BT (2008) Molecular landscape of modified histones in Drosophila heterochromatic genes and euchromatin-heterochromatin transition zones. PLoS Genet 4: e16. doi: 10.1371/journal.pgen.0040016 18208336

67. Martin D, Brun C, Remy E, Mouren P, Thieffry D, et al. (2004) GOToolBox: functional analysis of gene datasets based on Gene Ontology. Genome Biol 5: R101. 15575967

68. Hulsen T, de Vlieg J, Alkema W (2008) BioVenn—a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams. BMC Genomics 9: 488. doi: 10.1186/1471-2164-9-488 18925949

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