Skip to main content

Advertisement

SpringerLink
Log in

Innate and intrinsic antiviral immunity in Drosophila

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The fruit fly Drosophila melanogaster has been a valuable model to investigate the genetic mechanisms of innate immunity. Initially focused on the resistance to bacteria and fungi, these studies have been extended to include antiviral immunity over the last decade. Like all living organisms, insects are continually exposed to viruses and have developed efficient defense mechanisms. We review here our current understanding on antiviral host defense in fruit flies. A major antiviral defense in Drosophila is RNA interference, in particular the small interfering (si) RNA pathway. In addition, complex inducible responses and restriction factors contribute to the control of infections. Some of the genes involved in these pathways have been conserved through evolution, highlighting loci that may account for susceptibility to viral infections in humans. Other genes are not conserved and represent species-specific innovations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Bellen HJ, Yamamoto S (2015) Morgan’s legacy: fruit flies and the functional annotation of conserved genes. Cell 163:12–14. doi:10.1016/j.cell.2015.09.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hoffmann JA, Kafatos FC, Janeway CA, Ezekowitz RA (1999) Phylogenetic perspectives in innate immunity. Science 284:1313–1318

    Article  CAS  PubMed  Google Scholar 

  3. Medzhitov R, Janeway CAJ (2002) Decoding the patterns of self and nonself by the innate immune system. Science 296:298–300

    Article  CAS  PubMed  Google Scholar 

  4. Imler J-L, Bulet P (2005) Antimicrobial peptides in Drosophila: structures, activities and gene regulation. Chem Immunol Allergy 86:1–21. doi:10.1159/000086648

    Article  CAS  PubMed  Google Scholar 

  5. Hoffmann JA (2003) The immune response of Drosophila. Nature 426:33–38

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Veillard F, Troxler L, Reichhart J-M (2016) Drosophila melanogaster clip-domain serine proteases: structure, function and regulation. Biochimie 122:255–269. doi:10.1016/j.biochi.2015.10.007

    Article  CAS  PubMed  Google Scholar 

  8. Theopold U, Krautz R, Dushay MS (2014) The Drosophila clotting system and its messages for mammals. Dev Comp Immunol 42:42–46. doi:10.1016/j.dci.2013.03.014

    Article  CAS  PubMed  Google Scholar 

  9. Weavers H, Evans IR, Martin P, Wood W (2016) Corpse engulfment generates a molecular memory that primes the macrophage inflammatory response. Cell 165:1658–1671. doi:10.1016/j.cell.2016.04.049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gold KS, Brückner K (2015) Macrophages and cellular immunity in Drosophila melanogaster. Semin Immunol 27:357–368. doi:10.1016/j.smim.2016.03.010

    Article  CAS  PubMed  Google Scholar 

  11. Letourneau M, Lapraz F, Sharma A et al (2016) Drosophilahematopoiesis under normal conditions and in response to immune stress. FEBS Lett. doi:10.1002/1873-3468.12327

    PubMed  Google Scholar 

  12. Marques JT, Imler J-L (2016) The diversity of insect antiviral immunity: insights from viruses. Curr Opin Microbiol 32:71–76. doi:10.1016/j.mib.2016.05.002

    Article  CAS  PubMed  Google Scholar 

  13. Bronkhorst AW, van Rij RP (2014) The long and short of antiviral defense: small RNA-based immunity in insects. Current Opin Virol 7:19–28. doi:10.1016/j.coviro.2014.03.010

    Article  Google Scholar 

  14. Karlikow M, Goic B, Saleh M-C (2014) RNAi and antiviral defense in Drosophila: setting up a systemic immune response. Dev Comp Immunol 42:85–92. doi:10.1016/j.dci.2013.05.004

    Article  CAS  PubMed  Google Scholar 

  15. Xu J, Cherry S (2014) Viruses and antiviral immunity in Drosophila. Dev Comp Immunol 42:67–84. doi:10.1016/j.dci.2013.05.002

    Article  PubMed  CAS  Google Scholar 

  16. Kingsolver MB, Huang Z, Hardy RW (2013) Insect antiviral innate immunity: pathways, effectors, and connections. J Mol Biol 425:4921–4936. doi:10.1016/j.jmb.2013.10.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ding SW, Ding S-W (2010) RNA-based antiviral immunity. Nat Rev Immunol 10:632–644. doi:10.1038/nri2824

    Article  CAS  PubMed  Google Scholar 

  18. Lamiable O, Imler J-L (2014) Induced antiviral innate immunity in Drosophila. Curr Opin Microbiol 20:62–68. doi:10.1016/j.mib.2014.05.006

    Article  CAS  PubMed  Google Scholar 

  19. Ratcliff F (1997) A similarity between viral defense and gene silencing in plants. Science 276:1558–1560. doi:10.1126/science.276.5318.1558

    Article  CAS  PubMed  Google Scholar 

  20. Fire A, Fire A, Xu S et al (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811. doi:10.1038/35888

    Article  CAS  PubMed  Google Scholar 

  21. Berezikov E, Robine N, Samsonova A et al (2011) Deep annotation of Drosophila melanogaster microRNAs yields insights into their processing, modification, and emergence. Genome Res 21:203–215. doi:10.1101/gr.116657.110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Carthew RW, Agbu P, Giri R (2016) MicroRNA function in Drosophila melanogaster. Semin Cell Dev Biol. doi:10.1016/j.semcdb.2016.03.015

    PubMed  Google Scholar 

  23. Landthaler M, Yalcin A, Tuschl T (2004) The human DiGeorge syndrome critical region gene 8 and Its D. melanogaster homolog are required for miRNA biogenesis. Curr Biol 14:2162–2167. doi:10.1016/j.cub.2004.11.001

    Article  CAS  PubMed  Google Scholar 

  24. Marques JT, Kim K, Wu P-H et al (2009) Loqs and R2D2 act sequentially in the siRNA pathway in Drosophila. Nat Struct Mol Biol 17:24–30. doi:10.1038/nsmb.1735

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Saito K, Ishizuka A, Siomi H, Siomi MC (2005) Processing of pre-microRNAs by the Dicer-1–Loquacious complex in Drosophila cells. PLoS Biol 3:e235. doi:10.1371/journal.pbio.0030235

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Kwon SC, Nguyen TA, Choi Y-G et al (2016) Structure of human DROSHA. Cell 164:81–90. doi:10.1016/j.cell.2015.12.019

    Article  CAS  PubMed  Google Scholar 

  27. Förstemann K, Horwich MD, Wee L et al (2007) Drosophila microRNAs are sorted into functionally distinct argonaute complexes after production by Dicer-1. Cell 130:287–297. doi:10.1016/j.cell.2007.05.056

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Skalsky RL, Cullen BR (2010) Viruses, microRNAs, and host interactions. Annu Rev Microbiol 64:123–141. doi:10.1146/annurev.micro.112408.134243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hussain M, Asgari S (2014) MicroRNAs as mediators of insect host–pathogen interactions and immunity. J Insect Physiol 70:151–158. doi:10.1016/j.jinsphys.2014.08.003

    Article  CAS  PubMed  Google Scholar 

  30. Webster CL, Waldron FM, Robertson S et al (2015) The discovery, distribution, and evolution of viruses associated with Drosophila melanogaster. PLoS Biol 13:e1002210. doi:10.1371/journal.pbio.1002210

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Weber F, Wagner V, Rasmussen SB et al (2006) Double-stranded RNA is produced by positive-strand RNA viruses and DNA viruses but not in detectable amounts by negative-strand RNA viruses. J Virol 80:5059–5064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mueller S, Gausson V, Vodovar N et al (2010) RNAi-mediated immunity provides strong protection against the negative-strand RNA vesicular stomatitis virus in Drosophila. Proc Natl Acad Sci USA 107:19390–19395. doi:10.1073/pnas.1014378107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sabin LR, Zheng Q, Thekkat P et al (2013) Dicer-2 processes diverse viral RNA species. PLoS One 8:e55458. doi:10.1371/journal.pone.0055458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Son K-N, Liang Z, Lipton HL (2015) Double-stranded rna is detected by immunofluorescence analysis in RNA and DNA virus infections, including those by negative-stranded RNA viruses. J Virol 89:9383–9392. doi:10.1128/JVI.01299-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kemp C, Mueller S, Goto A 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

    Article  CAS  PubMed  Google Scholar 

  36. Bronkhorst AW, van Cleef KWR, Vodovar N et al (2012) The DNA virus invertebrate iridescent virus 6 is a target of the Drosophila RNAi machinery. Proc Natl Acad Sci USA 109:E3604–E3613. doi:10.1073/pnas.1207213109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Marques JT, Wang J-P, Wang X et al (2013) Functional specialization of the small interfering RNA pathway in response to virus infection. PLoS Pathog 9:e1003579. doi:10.1371/journal.ppat.1003579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Malone CD, Malone CD, Brennecke J et al (2009) Specialized piRNA pathways act in germline and somatic tissues of the Drosophila ovary. Cell 137:522–535. doi:10.1016/j.cell.2009.03.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Brennecke J, Aravin AA, Stark A et al (2007) Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128:1089–1103

    Article  CAS  PubMed  Google Scholar 

  40. Wang H, Ma Z, Niu K, et al (2016) Antagonistic roles of Nibbler and Hen1 in modulating piRNA 3′ ends in Drosophila. Development 143:530–539. doi:10.1242/dev.128116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vodovar N, Bronkhorst AW, van Cleef KWR et al (2012) Arbovirus-derived piRNAs exhibit a ping-pong signature in mosquito cells. PLoS One 7:e30861. doi:10.1371/journal.pone.0030861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Morazzani EM, Wiley MR, Murreddu MG et al (2012) Production of virus-derived ping-pong-dependent piRNA-like small RNAs in the mosquito soma. PLoS Pathog 8:e1002470. doi:10.1371/journal.ppat.1002470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Léger P, Lara E, Jagla B et al (2013) Dicer-2- and Piwi-mediated RNA interference in Rift Valley fever virus-infected mosquito cells. J Virol 87:1631–1648. doi:10.1128/JVI.02795-12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Miesen P, Girardi E, van Rij RP (2015) Distinct sets of PIWI proteins produce arbovirus and transposon-derived piRNAs in Aedes aegypti mosquito cells. Nucleic Acids Res 43:6545–6556. doi:10.1093/nar/gkv590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schnettler E, Donald CL, Human S et al (2013) Knockdown of piRNA pathway proteins results in enhanced Semliki Forest virus production in mosquito cells. J Gen Virol 94:1680–1689. doi:10.1099/vir.0.053850-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Aguiar ERGR, Olmo RP, Paro S et al (2015) Sequence-independent characterization of viruses based on the pattern of viral small RNAs produced by the host. Nucleic Acids Res 43(13):6191–6206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wu Q, Luo Y, Lu R et al (2010) Virus discovery by deep sequencing and assembly of virus-derived small silencing RNAs. Proc Natl Acad Sci 107:1606–1611. doi:10.1073/pnas.0911353107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Petit M, Mongelli V, Frangeul L et al (2016) piRNA pathway is not required for antiviral defense in Drosophila melanogaster. Proc Natl Acad Sci USA 113:E4218–E4227. doi:10.1073/pnas.1607952113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Iwasaki S, Sasaki HM, Sakaguchi Y et al (2015) Defining fundamental steps in the assembly of the Drosophila RNAi enzyme complex. Nature 521:533–536. doi:10.1038/nature14254

    Article  CAS  PubMed  Google Scholar 

  50. Liang C, Wang Y, Murota Y et al (2015) TAF11 assembles the RISC loading complex to enhance RNAi efficiency. Mol Cell 59:807–818. doi:10.1016/j.molcel.2015.07.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Nishida KM, Miyoshi K, Ogino A et al (2013) Roles of R2D2, a cytoplasmic D2 body component, in the endogenous siRNA pathway in Drosophila. Mol Cell 49:680–691. doi:10.1016/j.molcel.2012.12.024

    Article  CAS  PubMed  Google Scholar 

  52. Spellberg MJ, Marr MT, Marr MT II (2015) FOXO regulates RNA interference in Drosophilaand protects from RNA virus infection. Proc Natl Acad Sci 112:14587–14592. doi:10.1073/pnas.1517124112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Durdevic Z, Mobin MB, Hanna K, et al (2013) The RNA methyltransferase Dnmt2 is required for efficient Dicer-2-dependent siRNA pathway activity in Drosophila. Cell Rep 4:931–937. doi:10.1016/j.celrep.2013.07.046

    Article  CAS  PubMed  Google Scholar 

  54. Durdevic Z, Hanna K, Gold B et al (2013) Efficient RNA virus control in Drosophila requires the RNA methyltransferase Dnmt2. EMBO Rep 14:269–275. doi:10.1038/embor.2013.3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. van Rij RP, Saleh M-C, Berry B et al (2006) The RNA silencing endonuclease Argonaute 2 mediates specific antiviral immunity in Drosophila melanogaster. Genes Dev 20:2985–2995. doi:10.1101/gad.1482006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. van Cleef KWR, van Mierlo JT, Miesen P et al (2014) Mosquito and Drosophila entomobirnaviruses suppress dsRNA- and siRNA-induced RNAi. Nucleic Acids Res 42:8732–8744. doi:10.1093/nar/gku528

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Bronkhorst AW, van Cleef KWR, Venselaar H, van Rij RP (2014) A dsRNA-binding protein of a complex invertebrate DNA virus suppresses the Drosophila RNAi response. Nucleic Acids Res 42:12237–12248. doi:10.1093/nar/gku910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chao JA, Lee JH, Chapados BR et al (2005) Dual modes of RNA-silencing suppression by Flock House virus protein B2. Nat Struct Mol Biol 12:952–957

    Article  CAS  PubMed  Google Scholar 

  59. Han YH, Luo YJ, Wu Q et al (2011) RNA-based immunity terminates viral infection in adult Drosophila in the absence of viral suppression of RNA interference: characterization of viral small interfering RNA populations in wild-type and mutant flies. J Virol 85:13153–13163. doi:10.1128/JVI.05518-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Petrillo JE, Petrillo JE, Venter PA et al (2013) Cytoplasmic granule formation and translational inhibition of nodaviral RNAs in the absence of the double-stranded RNA binding protein B2. J Virol 87:13409–13421. doi:10.1128/JVI.02362-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Obbard DJ, Jiggins FM, Halligan DL, Little TJ (2006) Natural selection drives extremely rapid evolution in antiviral RNAi genes. Curr Biol 16:580–585

    Article  CAS  PubMed  Google Scholar 

  62. van Mierlo JT, Overheul GJ, Obadia B et al (2014) Novel Drosophila viruses encode host-specific suppressors of RNAi. PLoS Pathog 10:e1004256. doi:10.1371/journal.ppat.1004256

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Roignant J-Y, Carré C, Mugat B et al (2003) Absence of transitive and systemic pathways allows cell-specific and isoform-specific RNAi in Drosophila. RNA 9:299–308. doi:10.1261/rna.2154103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Longdon B, Cao C, Martinez J, Jiggins FM (2013) Previous exposure to an RNA virus does not protect against subsequent infection in Drosophila melanogaster. PLoS One 8:e73833. doi:10.1371/journal.pone.0073833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Saleh M-C, Tassetto M, van Rij RP et al (2009) Antiviral immunity in Drosophila requires systemic RNA interference spread. Nature 458:346–350. doi:10.1038/nature07712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Saleh M-C, van Rij RP, Hekele A et al (2006) The endocytic pathway mediates cell entry of dsRNA to induce RNAi silencing. Nat Cell Biol 8:793–802. doi:10.1038/ncb1439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Goic B, Vodovar N, Mondotte JA et al (2013) RNA-mediated interference and reverse transcription control the persistence of RNA viruses in the insect model Drosophila. Nat Immunol 14:396–403. doi:10.1038/ni.2542

    Article  CAS  PubMed  Google Scholar 

  68. Karlikow M, Goic B, Mongelli V, et al (2016) Drosophila cells use nanotube-like structures to transfer dsRNA and RNAi machinery between cells. Sci Rep 6:27085. doi:10.1038/srep27085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Valanne S, Wang J-H, Rämet M (2011) The Drosophila Toll signaling pathway. J Immunol 186:649–656. doi:10.4049/jimmunol.1002302

    Article  CAS  PubMed  Google Scholar 

  70. Kleino A, Silverman N (2014) The Drosophila IMD pathway in the activation of the humoral immune response. Dev Comp Immunol 42:25–35. doi:10.1016/j.dci.2013.05.014

    Article  CAS  PubMed  Google Scholar 

  71. Zeidler MP, Bausek N (2013) The Drosophila JAK-STAT pathway. JAKSTAT 2:e25353. doi:10.4161/jkst.25353

    PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  73. Merkling SH, Bronkhorst AW, Kramer JM et al (2015) The epigenetic regulator G9a mediates tolerance to RNA virus infection in Drosophila. PLoS Pathog 11:e1004692. doi:10.1371/journal.ppat.1004692

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Zambon RA, Nandakumar M, Vakharia VN, Wu LP (2005) The Toll pathway is important for an antiviral response in Drosophila. Proc Natl Acad Sci 102:7257–7262. doi:10.1073/pnas.0409181102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ferreira ÁG, Naylor H, Esteves SS 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Bitra K, Suderman RJ, Strand MR (2012) Polydnavirus Ank proteins bind NF-κB homodimers and inhibit processing of Relish. PLoS Pathog 8:e1002722. doi:10.1371/journal.ppat.1002722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gueguen G, Kalamarz ME, Ramroop J et al (2013) Polydnaviral ankyrin proteins aid parasitic wasp survival by coordinate and selective inhibition of hematopoietic and immune NF-kappa B signaling in insect hosts. PLoS Pathog 9:e1003580. doi:10.1371/journal.ppat.1003580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Avadhanula V, Weasner BP, Hardy GG et al (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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Costa A, Jan E, Sarnow P, Schneider D (2009) The Imd pathway is involved in antiviral immune responses in Drosophila. PLoS ONE 4:e7436. doi:10.1371/journal.pone.0007436

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Huang Z, Kingsolver MB, Avadhanula V, Hardy RW (2013) An antiviral role for antimicrobial peptides during the arthropod response to alphavirus replication. J Virol 87:4272–4280. doi:10.1128/JVI.03360-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lamiable O, Kellenberger C, Kemp C et al (2016) Cytokine Diedel and a viral homologue suppress the IMD pathway in Drosophila. Proc Natl Acad Sci USA 113:698–703. doi:10.1073/pnas.1516122113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Merkling SH, Overheul GJ, van Mierlo JT, et al (2015) The heat shock response restricts virus infection in Drosophila. Sci Rep 5:12758. doi:10.1038/srep12758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Xu J, Grant G, Sabin LR et al (2012) Transcriptional pausing controls a rapid antiviral innate immune response in Drosophila. Cell Host Microbe 12:531–543. doi:10.1016/j.chom.2012.08.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Xu J, Hopkins K, Sabin L et al (2013) ERK signaling couples nutrient status to antiviral defense in the insect gut. Proc Natl Acad Sci USA 110:15025–15030. doi:10.1073/pnas.1303193110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sansone CL, Cohen J, Yasunaga A et al (2015) Microbiota-dependent priming of antiviral intestinal immunity in Drosophila. Cell Host Microbe 18:571–581. doi:10.1016/j.chom.2015.10.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Goubau D, Deddouche S, Reis e Sousa C (2013) Cytosolic sensing of viruses. Immunity 38:855–869. doi:10.1016/j.immuni.2013.05.007

    Article  CAS  PubMed  Google Scholar 

  87. Deddouche S, Matt N, Budd A 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 0.1664

    Article  CAS  PubMed  Google Scholar 

  88. Paradkar PN, Trinidad L, Voysey R et al (2012) Secreted Vago restricts West Nile virus infection in Culex mosquito cells by activating the Jak-STAT pathway. Proc Natl Acad Sci USA 109:18915–18920. doi:10.1073/pnas.1205231109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Paro S, Imler J-L, Meignin C (2015) Sensing viral RNAs by Dicer/RIG-I like ATPases across species. Curr Opin Immunol 32:106–113. doi:10.1016/j.coi.2015.01.009

    Article  CAS  PubMed  Google Scholar 

  90. Paradkar PN, Duchemin J-B, Voysey R, Walker PJ (2014) Dicer-2-dependent activation of Culex Vago occurs via the TRAF-Rel2 signaling pathway. PLoS Negl Trop Dis 8:e2823. doi:10.1371/journal.pntd.0002823

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Mukae N, Yokoyama H, Yokokura T et al (2002) Activation of the innate immunity in Drosophila by endogenous chromosomal DNA that escaped apoptotic degradation. Genes Dev 16:2662–2671. doi:10.1101/gad.1022802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Liu X, Sano T, Guan Y et al (2012) Drosophila EYA regulates the immune response against DNA through an evolutionarily conserved threonine phosphatase motif. PLoS One 7:e42725. doi:10.1371/journal.pone.0042725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ming M, Obata F, Kuranaga E, Miura M (2014) Persephone/Spätzle pathogen sensors mediate the activation of Toll receptor signaling in response to endogenous danger signals in apoptosis-deficient Drosophila. J Biol Chem 289:7558–7568. doi:10.1074/jbc.M113.543884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Clem RJ (2015) Viral IAPs, then and now. Semin Cell Dev Biol 39:72–79. doi:10.1016/j.semcdb.2015.01.011

    Article  CAS  PubMed  Google Scholar 

  95. Garrey JL, Lee Y-Y, Au HHT et al (2010) Host and viral translational mechanisms during cricket paralysis virus infection. J Virol 84:1124–1138. doi:10.1128/JVI.02006-09

    Article  CAS  PubMed  Google Scholar 

  96. Chtarbanova S, Lamiable O, Lee K-Z et al (2014) Drosophila C virus systemic infection leads to intestinal obstruction. J Virol 88:14057–14069. doi:10.1128/JVI.02320-14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Becker T, Loch G, Beyer M et al (2010) FOXO-dependent regulation of innate immune homeostasis. Nature 463:369–373. doi:10.1038/nature08698

    Article  CAS  PubMed  Google Scholar 

  98. Panda D, Pascual-Garcia P, Dunagin M et al (2014) Nup98 promotes antiviral gene expression to restrict RNA viral infection in Drosophila. Proc Natl Acad Sci USA 111:E3890–E3899. doi:10.1073/pnas.1410087111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Panda D, Gold B, Tartell MA, et al (2015) The transcription factor FoxK participates with Nup98 to regulate antiviral gene expression. MBio 6:e02509–14. doi:10.1128/mBio.02509-14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Klotman ME, Chang TL (2006) Defensins in innate antiviral immunity. Nat Rev Immunol 6:447–456. doi:10.1038/nri1860

    Article  CAS  PubMed  Google Scholar 

  101. Luplertlop N, Surasombatpattana P, Patramool S et al (2011) Induction of a peptide with activity against a broad spectrum of pathogens in the Aedes aegypti salivary gland, following infection with dengue virus. PLoS Pathog 7:e1001252. doi:10.1371/journal.ppat.1001252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Souza-Neto JA, Sim S, Dimopoulos G (2009) An evolutionary conserved function of the JAK-STAT pathway in anti-dengue defense. Proc Natl Acad Sci USA 106:17841–17846. doi:10.1073/pnas.0905006106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Settles EW, Friesen PD (2008) Flock house virus induces apoptosis by depletion of Drosophila inhibitor-of-apoptosis protein DIAP1. J Virol 82:1378–1388

    Article  CAS  PubMed  Google Scholar 

  104. Liu B, Behura SK, Clem RJ et al (2013) P53-mediated rapid induction of apoptosis conveys resistance to viral infection in Drosophila melanogaster. PLoS Pathog 9:e1003137. doi:10.1371/journal.ppat.1003137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lamiable O, Arnold J, de Faria IJDS et al (2016) Analysis of the contribution of hemocytes and autophagy to Drosophila antiviral immunity. J Virol 90:5415–5426. doi:10.1128/JVI.00238-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Nainu F, Nainu F, Tanaka Y et al (2015) Protection of insects against viral infection by apoptosis-dependent phagocytosis. J Immunol 195:5696–5706. doi:10.4049/jimmunol.1500613

    Article  CAS  PubMed  Google Scholar 

  107. Kluge SF, Sauter D, Kirchhoff F (2015) SnapShot: antiviral restriction factors. Cell 163(774–774):e1. doi:10.1016/j.cell.2015.10.019

    Google Scholar 

  108. Duggal NK, Emerman M (2012) Evolutionary conflicts between viruses and restriction factors shape immunity. Nat Rev Immunol 12:687–695. doi:10.1038/nri3295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Harris RS, Hultquist JF, Evans DT (2012) The restriction factors of human immunodeficiency virus. J Biol Chem 287:40875–40883. doi:10.1074/jbc.R112.416925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. van Montfoort N, Olagnier D, Hiscott J (2014) Unmasking immune sensing of retroviruses: Interplay between innate sensors and host effectors. Cytokine Growth Factor Rev 25:657–668. doi:10.1016/j.cytogfr.2014.08.006

    Article  PubMed  CAS  Google Scholar 

  111. Smith RM, Pernstich C, Halford SE (2014) TstI, a Type II restriction-modification protein with DNA recognition, cleavage and methylation functions in a single polypeptide. Nucleic Acids Res 42:5809–5822. doi:10.1093/nar/gku187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Simon V, Bloch N, Landau NR (2015) Intrinsic host restrictions to HIV-1 and mechanisms of viral escape. Nat Immunol 16:546–553. doi:10.1038/ni.3156

    Article  CAS  PubMed  Google Scholar 

  113. Jia X, Zhao Q, Xiong Y (2015) HIV suppression by host restriction factors and viral immune evasion. Curr Opin Struct Biol 31:106–114. doi:10.1016/j.sbi.2015.04.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zhou L-Y (2016) Host restriction factors for hepatitis C virus. World J Gastroenterol 22:1477. doi:10.3748/wjg.v22.i4.1477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Cogni R, Cao C, Day JP et al (2016) The genetic architecture of resistance to virus infection in Drosophila. Mol Ecol. doi:10.1111/mec.13769

    PubMed  PubMed Central  Google Scholar 

  116. Gay P (1978) Drosophila genes which intervene in multiplication of sigma virus. Mol Gen Genet 159:269–283. doi:10.1007/BF00268263

    Article  CAS  PubMed  Google Scholar 

  117. Lhéritier P (1958) The hereditary virus of Drosophila. In: Advances in virus research, vol 5. Elsevier, Amsterdam, pp 195–245

  118. Contamine D, Petitjean AM, Ashburner M (1989) Genetic resistance to viral infection: the molecular cloning of a Drosophila gene that restricts infection by the rhabdovirus sigma. Genetics 123:525–533

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Wayne ML, Contamine D, Kreitman M (1996) Molecular population genetics of ref(2)P, a locus which confers viral resistance in Drosophila. Mol Biol Evol 13:191–199

    Article  CAS  PubMed  Google Scholar 

  120. Dru P, Bras F, Dezélée S et al (1993) Unusual variability of the Drosophila melanogaster ref(2)P protein which controls the multiplication of sigma rhabdovirus. Genetics 133:943–954

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Wyers F, Dru P, Simonet B, Contamine D (1993) Immunological cross-reactions and interactions between the Drosophila melanogaster ref(2)P protein and sigma rhabdovirus proteins. J Virol 67:3208–3216

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Contamine D (1981) Role of the Drosophila genome in Sigma virus multiplication. I. Role of the ret(2)P gene; selection of host-adapted mutants at the nonpermissive allele Pp. Virology 114:474–488

    Article  CAS  PubMed  Google Scholar 

  123. Fleuriet A, Periquet G (1993) Evolution of the Drosophila melanogaster-sigma virus system in natural populations from Languedoc (southern France). Arch Virol 129:131–143

    Article  CAS  PubMed  Google Scholar 

  124. Carré-Mlouka A, Gaumer S, Gay P et al (2007) Control of sigma virus multiplication by the ref(2)P gene of Drosophila melanogaster: an in vivo study of the PB1 domain of Ref(2)P. Genetics 176:409–419. doi:10.1534/genetics.106.063826

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Avila A, Silverman N, Diaz-Meco MT, Moscat J (2002) The Drosophila atypical protein kinase C-ref(2)p complex constitutes a conserved module for signaling in the toll pathway. Mol Cell Biol 22:8787–8795. doi:10.1128/MCB.22.24.8787-8795.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Goto A, Blandin S, Royet J et al (2003) Silencing of Toll pathway components by direct injection of double-stranded RNA into Drosophila adult flies. Nucleic Acids Res 31:6619–6623. doi:10.1093/nar/gkg852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ktistakis NT, Tooze SA (2016) Digesting the expanding mechanisms of autophagy. Trends Cell Biol 26:624–635. doi:10.1016/j.tcb.2016.03.006

    Article  CAS  PubMed  Google Scholar 

  128. Nezis IP, Simonsen A, Sagona AP et al (2008) Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain. J Cell Biol 180:1065–1071. doi:10.1083/jcb.200711108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Shelly S, Lukinova N, Bambina S et al (2009) Autophagy is an essential component of Drosophila immunity against vesicular stomatitis virus. Immunity 30:588–598. doi:10.1016/j.immuni.2009.02.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Joubert P-E, Meiffren G, Grégoire IP et al (2009) Autophagy induction by the pathogen receptor CD46. Cell Host Microbe 6:354–366. doi:10.1016/j.chom.2009.09.006

    Article  PubMed  CAS  Google Scholar 

  131. Richetta C, Faure M (2013) Autophagy in antiviral innate immunity. Cell Microbiol 15:368–376. doi:10.1111/cmi.12043

    Article  CAS  PubMed  Google Scholar 

  132. Richetta C, Grégoire IP, Verlhac P et al (2013) Sustained autophagy contributes to measles virus infectivity. PLoS Pathog 9:e1003599. doi:10.1371/journal.ppat.1003599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Mauthe M, Langereis M, Jung J et al (2016) An siRNA screen for ATG protein depletion reveals the extent of the unconventional functions of the autophagy proteome in virus replication. J Cell Biol 214:619–635. doi:10.1083/jcb.201602046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Cao C, Magwire MM, Bayer F, Jiggins FM (2016) A polymorphism in the processing body component Ge-1 controls resistance to a naturally occurring rhabdovirus in Drosophila. PLoS Pathog 12:e1005387. doi:10.1371/journal.ppat.1005387

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Yu JH, Yang W-H, Gulick T et al (2005) Ge-1 is a central component of the mammalian cytoplasmic mRNA processing body. RNA 11:1795–1802. doi:10.1261/rna.2142405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Xu J, Yang J-Y, Niu Q-W, Chua N-H (2006) Arabidopsis DCP2, DCP1, and VARICOSE form a decapping complex required for postembryonic development. Plant Cell 18:3386–3398. doi:10.1105/tpc.106.047605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Hopkins KC, McLane LM, Maqbool T et al (2013) A genome-wide RNAi screen reveals that mRNA decapping restricts bunyaviral replication by limiting the pools of Dcp2-accessible targets for cap-snatching. Genes Dev 27:1511–1525. doi:10.1101/gad.215384.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Magwire MM, Bayer F, Webster CL et al (2011) Successive increases in the resistance of Drosophila to viral infection through a transposon insertion followed by a duplication. PLoS Genet 7:e1002337. doi:10.1371/journal.pgen.1002337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Magwire MM, Fabian DK, Schweyen H et al (2012) Genome-wide association studies reveal a simple genetic basis of resistance to naturally coevolving viruses in Drosophila melanogaster. PLoS Genet 8:e1003057. doi:10.1371/journal.pgen.1003057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Martins NE, Faria VG, Nolte V et al (2014) Host adaptation to viruses relies on few genes with different cross-resistance properties. Proc Natl Acad Sci USA 111:5938–5943. doi:10.1073/pnas.1400378111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Doyle T, Goujon C, Malim MH (2015) HIV-1 and interferons: who’s interfering with whom? Nat Rev Microbiol 13:403–413. doi:10.1038/nrmicro3449

    Article  CAS  PubMed  Google Scholar 

  142. Moy RH, Cole BS, Yasunaga A et al (2014) Stem-loop recognition by DDX17 facilitates miRNA processing and antiviral defense. Cell 158:764–777. doi:10.1016/j.cell.2014.06.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Yasunaga A, Hanna SL, Li J et al (2014) Genome-wide RNAi screen identifies broadly-acting host factors that inhibit arbovirus infection. PLoS Pathog 10:e1003914. doi:10.1371/journal.ppat.1003914

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Shapiro JS, Schmid S, Aguado LC et al (2014) Drosha as an interferon-independent antiviral factor. Proc Natl Acad Sci USA 111:7108–7113. doi:10.1073/pnas.1319635111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Molleston JM, Sabin LR, Moy RH et al (2016) A conserved virus-induced cytoplasmic TRAMP-like complex recruits the exosome to target viral RNA for degradation. Genes Dev 30:1658–1670. doi:10.1101/gad.284604.116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Faria VG, Martins NE, Magalhães S et al (2016) Drosophila adaptation to viral infection through defensive symbiont evolution. PLoS Genet 12:e1006297. doi:10.1371/journal.pgen.1006297

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Wong ZS, Brownlie JC, Johnson KN (2016) Impact of ERK activation on fly survival and Wolbachia-mediated protection during virus infection. J Gen Virol 97:1446–1452. doi:10.1099/jgv.0.000456

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Nelson Martins and Dr. David Gubb for critical reading and comments on the manuscript and Dr. Carine Meignin for help with the figures. Work in our laboratory was supported by CNRS and grants from NIH (PO1 AI070167), ANR (ANR-13-BSV3-009), Infect-ERA (ANR-14-IFEC-0005), and Investissements d’Avenir Programs (ANR-10-LABX-36 ; ANR-11-EQPX-0022).

Author information

Authors and Affiliations

  1. Institut de Biologie Moléculaire et Cellulaire, CNRS UPR9022, Université de Strasbourg, 15 rue René Descartes, 67000, Strasbourg, France

    Assel Mussabekova, Laurent Daeffler & Jean-Luc Imler

  2. Faculté des Sciences de la Vie, Université de Strasbourg, 28 rue Goethe, 67000, Strasbourg, France

    Jean-Luc Imler

Authors
  1. Assel Mussabekova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laurent Daeffler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean-Luc Imler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Assel Mussabekova.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mussabekova, A., Daeffler, L. & Imler, JL. Innate and intrinsic antiviral immunity in Drosophila. Cell. Mol. Life Sci. 74, 2039–2054 (2017). https://doi.org/10.1007/s00018-017-2453-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-017-2453-9

Keywords

Search

Navigation