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The Jak-STAT signaling pathway is required but not sufficient for the antiviral response of drosophila

Nature Immunology volume 6, pages 946–953 (2005)Cite this article

Abstract

The response of drosophila to bacterial and fungal infections involves two signaling pathways, Toll and Imd, which both activate members of the transcription factor NF-κB family. Here we have studied the global transcriptional response of flies to infection with drosophila C virus. Viral infection induced a set of genes distinct from those regulated by the Toll or Imd pathways and triggered a signal transducer and activator of transcription (STAT) DNA-binding activity. Genetic experiments showed that the Jak kinase Hopscotch was involved in the control of the viral load in infected flies and was required but not sufficient for the induction of some virus-regulated genes. Our results indicate that in addition to Toll and Imd, a third, evolutionary conserved innate immunity pathway functions in drosophila and counters viral infection.

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Figure 1: DCV infection triggers a transcriptional response in drosophila.
Figure 2: Selective induction of vir-1 after virus infection.
Figure 3: Characterization of vir-1.
Figure 4: The vir-1 promoter is induced by DCV in the ventral epidermis but not in the fat body.
Figure 5: The Jak-STAT pathway is involved in the response to DCV infection.
Figure 6: The Jak-STAT pathway controls the viral load in DCV-infected flies and resistance to infection.

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References

  1. Hoffmann, J. The immune response of Drosophila . Nature 426, 33–38 (2003).

    Article  CAS  Google Scholar 

  2. Tzou, P., De Gregorio, E. & Lemaitre, B. How Drosophila combats microbial infection: a model to study innate immunity and host-pathogen interactions. Curr. Opin. Microbiol. 5, 102–110 (2002).

    Article  CAS  Google Scholar 

  3. Hultmark, D. Drosophila immunity: paths and patterns. Curr. Opin. Immunol. 15, 12–19 (2003).

    Article  CAS  Google Scholar 

  4. Silverman, N. & Maniatis, T. NF-κB signaling pathways in mammalian and insect innate immunity. Genes Dev. 15, 2321–2342 (2001).

    Article  CAS  Google Scholar 

  5. Brennan, C.A. & Anderson, K.V. Drosophila: the genetics of innate immune recognition and response. Annu. Rev. Immunol. 22, 457–483 (2004).

    Article  CAS  Google Scholar 

  6. Jousset, F.X., Bergoin, M. & Revet, B. Characterization of the Drosophila C virus. J. Gen. Virol. 34, 269–283 (1977).

    Article  CAS  Google Scholar 

  7. Keene, K.M. et al. RNA interference acts as a natural antiviral response to O'nyong-nyong virus (Alphavirus; Togaviridae) infection of Anopheles gambiae . Proc. Natl. Acad. Sci. USA 101, 17240–17245 (2004).

    Article  CAS  Google Scholar 

  8. Roxstrom-Lindquist, K., Terenius, O. & Faye, I. Parasite-specific immune response in adult Drosophila melanogaster: a genomic study. EMBO Rep. 5, 207–212 (2004).

    Article  Google Scholar 

  9. Mackenzie, J.S., Gubler, D.J. & Petersen, L.R. Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat. Med. 10, S98–S109 (2004).

    Article  CAS  Google Scholar 

  10. Cherry, S. & Perrimon, N. Entry is a rate-limiting step for viral infection in a Drosophila melanogaster model of pathogenesis. Nat. Immunol. 5, 81–87 (2004).

    Article  CAS  Google Scholar 

  11. Sabatier, L. et al. Pherokine-2 and -3: Two Drosophila molecules related to pheromone/odor-binding proteins induced by viral and bacterial infections. Eur. J. Biochem. 270, 3398–3407 (2003).

    Article  CAS  Google Scholar 

  12. Cherry, S. et al. Genome-wide RNAi screen reveals a specific sensitivity of IRES-containing RNA viruses to host translation inhibition. Genes Dev. 19, 445–452 (2005).

    Article  CAS  Google Scholar 

  13. Johnson, K.N. & Christian, P.D. The novel genome organization of the insect picorna-like virus Drosophila C virus suggests this virus belongs to a previously undescribed virus family. J. Gen. Virol. 79, 191–203 (1998).

    Article  CAS  Google Scholar 

  14. Yan, R., Small, S., Desplan, C., Dearolf, C.R. & Darnell, J.E., Jr. Identification of a Stat gene that functions in Drosophila development. Cell 84, 421–430 (1996).

    Article  CAS  Google Scholar 

  15. Perrimon, N. & Mahowald, A.P. l(1) hopscotch, a larval-pupal zygotic lethal with a specific maternal effect on segmentation in Drosophila . Dev. Biol. 118, 28–41 (1986).

    Article  CAS  Google Scholar 

  16. Irving, P. et al. A genome-wide analysis of immune responses in Drosophila . Proc. Natl. Acad. Sci. USA 98, 15119–15124 (2001).

    Article  CAS  Google Scholar 

  17. De Gregorio, E., Spellman, P.T., Rubin, G.M. & Lemaitre, B. Genome-wide analysis of the Drosophila immune response by using oligonucleotide microarrays. Proc. Natl. Acad. Sci. USA 98, 12590–12595 (2001).

    Article  CAS  Google Scholar 

  18. Boutros, M., Agaisse, H. & Perrimon, N. Sequential activation of signaling pathways during innate immune responses in Drosophila . Dev. Cell 3, 711–722 (2002).

    Article  CAS  Google Scholar 

  19. Ekengren, S. et al. A humoral stress response in Drosophila . Curr. Biol. 11, 714–718 (2001).

    Article  CAS  Google Scholar 

  20. Tihova, M. et al. Nodavirus coat protein imposes dodecahedral RNA structure independent of nucleotide sequence and length. J. Virol. 78, 2897–2905 (2004).

    Article  CAS  Google Scholar 

  21. Hou, S.X., Zheng, Z., Chen, X. & Perrimon, N. The Jak/STAT pathway in model organisms: emerging roles in cell movement. Dev. Cell 3, 765–778 (2002).

    Article  CAS  Google Scholar 

  22. Hombria, J.C. & Brown, S. The fertile field of Drosophila Jak/STAT signalling. Curr. Biol. 12, R569–R575 (2002).

    Article  Google Scholar 

  23. Agaisse, H., Petersen, U.M., Boutros, M., Mathey-Prevot, B. & Perrimon, N. Signaling role of hemocytes in Drosophila JAK/STAT-dependent response to septic injury. Dev. Cell 5, 441–450 (2003).

    Article  CAS  Google Scholar 

  24. Harrison, D., Binari, R., Stines Nahreini, T., Gilman, M. & Perrimon, N. Activation of a Drosophila Janus kinase (JAK) causes hematopoietic neoplasia and developmental defects. EMBO J. 14, 2857–2865 (1995).

    Article  CAS  Google Scholar 

  25. Luo, H., Hanratty, W. & Dearolf, C. An amino acid sustitution in the Drosophila hopTum-l Jak kinase causes leukemia-like hematopoietic defects. EMBO J. 14, 1412–1420 (1995).

    Article  CAS  Google Scholar 

  26. Brown, S., Hu, N. & Hombria, J.C. Identification of the first invertebrate interleukin JAK/STAT receptor, the Drosophila gene domeless. Curr. Biol. 11, 1700–1705 (2001).

    Article  CAS  Google Scholar 

  27. Chen, H.W. et al. mom identifies a receptor for the Drosophila JAK/STAT signal transduction pathway and encodes a protein distantly related to the mammalian cytokine receptor family. Genes Dev. 16, 388–398 (2002).

    Article  CAS  Google Scholar 

  28. Betz, A., Lampen, N., Martinek, S., Young, M.W. & Darnell, J.E., Jr. A Drosophila PIAS homologue negatively regulates stat92E. Proc. Natl. Acad. Sci. USA 98, 9563–9568 (2001).

    Article  CAS  Google Scholar 

  29. Brandt, S.M. et al. Secreted bacterial effectors and host-produced Eiger/TNF drive death in a salmonella-infected fruit fly. PLoS Biol. 2, 2067–2075 (2004).

    Article  CAS  Google Scholar 

  30. Ganz, T. Defensins: antimicrobial peptides of innate immunity. Nat. Rev. Immunol. 3, 710–720 (2003).

    Article  CAS  Google Scholar 

  31. Chinchar, V.G. et al. Inactivation of viruses infecting ectothermic animals by amphibian and piscine antimicrobial peptides. Virology 323, 268–275 (2004).

    Article  CAS  Google Scholar 

  32. Irusta, P.M., Chen, Y.B. & Hardwick, J.M. Viral modulators of cell death provide new links to old pathways. Curr. Opin. Cell Biol. 15, 700–705 (2003).

    Article  CAS  Google Scholar 

  33. Lecellier, C.H. & Voinnet, O. RNA silencing: no mercy for viruses? Immunol. Rev. 198, 285–303 (2004).

    Article  CAS  Google Scholar 

  34. Li, H., Li, W.X. & Ding, S.W. Induction and suppression of RNA silencing by an animal virus. Science 296, 1319–1321 (2002).

    Article  CAS  Google Scholar 

  35. Gobert, V. et al. Dual activation of the Drosophila toll pathway by two pattern recognition receptors. Science 302, 2126–2130 (2003).

    Article  CAS  Google Scholar 

  36. Pili-Floury, S. et al. In vivo RNA interference analysis reveals an unexpected role for GNBP1 in the defense against Gram-positive bacterial infection in Drosophila adults. J. Biol. Chem. 279, 12848–12853 (2004).

    Article  CAS  Google Scholar 

  37. Harvey, N.L. et al. Characterization of the Drosophila caspase, DAMM. J. Biol. Chem. 276, 25342–25350 (2001).

    Article  CAS  Google Scholar 

  38. Diveu, C. et al. GPL, a novel cytokine receptor related to GP130 and leukemia inhibitory factor receptor. J. Biol. Chem. 278, 49850–49859 (2003).

    Article  CAS  Google Scholar 

  39. Harrison, D.A., McCoon, P.E., Binari, R., Gilman, M. & Perrimon, N. Drosophila unpaired encodes a secreted protein that activates the JAK signaling pathway. Genes Dev. 12, 3252–3263 (1998).

    Article  CAS  Google Scholar 

  40. Barillas-Mury, C., Han, Y.S., Seeley, D. & Kafatos, F.C. Anopheles gambiae Ag-STAT, a new insect member of the STAT family, is activated in response to bacterial infection. EMBO J. 18, 959–967 (1999).

    Article  CAS  Google Scholar 

  41. Lagueux, M., Perrodou, E., Levashina, E.A., Capovilla, M. & Hoffmann, J.A. Constitutive expression of a complement-like protein in toll and JAK gain-of-function mutants of Drosophila . Proc. Natl. Acad. Sci. USA 97, 11427–11432 (2000).

    Article  CAS  Google Scholar 

  42. Lin, C.C. et al. Characterization of two mosquito STATs, AaSTAT and CtSTAT. Differential regulation of tyrosine phosphorylation and DNA binding activity by lipopolysaccharide treatment and by Japanese encephalitis virus infection. J. Biol. Chem. 279, 3308–3317 (2004).

    Article  CAS  Google Scholar 

  43. Silvennoinen, O., Ihle, J.N., Schlessinger, J. & Levy, D.E. Interferon-induced nuclear signalling by Jak protein tyrosine kinases. Nature 366, 583–585 (1993).

    Article  CAS  Google Scholar 

  44. Shuai, K. et al. Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins. Nature 366, 580–583 (1993).

    Article  CAS  Google Scholar 

  45. Watling, D. et al. Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-γ signal transduction pathway. Nature 366, 166–170 (1993).

    Article  CAS  Google Scholar 

  46. Dupuis, S. et al. Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency. Nat. Genet. 33, 388–391 (2003).

    Article  CAS  Google Scholar 

  47. Karst, S.M., Wobus, C.E., Lay, M., Davidson, J. & Virgin, H.W. 4th. STAT1-dependent innate immunity to a Norwalk-like virus. Science 299, 1575–1578 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  49. Jung, A.C., Criqui, M.C., Rutschmann, S., Hoffmann, J.A. & Ferrandon, D. Microfluorometer assay to measure the expression of β-galactosidase and green fluorescent protein reporter genes in single Drosophila flies. Biotechniques 30, 594–8, 600–1 (2001).

    Article  CAS  Google Scholar 

  50. Gottar, M. et al. The Drosophila immune response against Gram-negative bacteria is mediated by a peptidoglycan recognition protein. Nature 416, 640–644 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Ozkan for help with transgenesis; M.-C. Lacombe for assistance with real-time quantitative RT-PCR analysis; J. Mutterer and D. Zachary for help with the confocal microscopy; E. Santiago for technical support; D. Ferrandon and J. Royet for discussions and critical reading of the manuscript; N. Perrimon, J. Castelli-Gair Hombria and J. Darnell for providing fly stocks; and A. Schneemann for the FHV stock and discussions. Supported by Centre National de la Recherche Scientifique and Ministère de la Recherche et de la Technologie (Actions Concertées Incitatives Physiologie Intégrative and Microbiologie, and Programme puces Affymetrix); Institut Universitaire de France; Ligue contre le Cancer (E.J.); Centre National de la Recherche Scientifique (D.G.A.); and Ministère de la Recherche du Grand-Duché de Luxembourg (C.D.).

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  1. Emmanuelle Jouanguy

    Present address: Institut National de la Santé et de la Recherche Médicale U550, Faculté Necker, 75015, Paris, France

Authors and Affiliations

  1. Centre National de la Recherche Scientifique UPR9022, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, 67000, France

    Catherine Dostert, Emmanuelle Jouanguy, Phil Irving, Laurent Troxler, Delphine Galiana-Arnoux, Charles Hetru, Jules A Hoffmann & Jean-Luc Imler

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Supplementary information

Supplementary Fig. 1

Susceptibility of wild-type flies to DCV infection. (PDF 98 kb)

Supplementary Fig. 2

DCV infection upregulates expression of genes across a broad range of functional categories. (PDF 56 kb)

Supplementary Fig. 3

Characterization of the vir-1 transcript and promoter. (PDF 112 kb)

Supplementary Fig. 4

Constitutive activity of the vir-1 promoter in S2 cells is dependent on the presence of a consensus STAT92E binding site at position -342. (PDF 91 kb)

Supplementary Fig. 5

Susceptibility of wild-type and hopM38/msvl mutant flies to infection with different doses of DCV. (PDF 93 kb)

Supplementary Table 1

Genes up-regulated at least two-fold or induced by DCV infection. (PDF 91 kb)

Supplementary Table 2

Sequence and position of the STAT92E consensus binding sites in the promoters of the virus-regulated genes vir-1, CG12780, and CG9080. (PDF 76 kb)

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Dostert, C., Jouanguy, E., Irving, P. et al. The Jak-STAT signaling pathway is required but not sufficient for the antiviral response of drosophila. Nat Immunol 6, 946–953 (2005). https://doi.org/10.1038/ni1237

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