Nematoda: The Caenorhabditis elegans Model for Innate Immunity – Interactions Between Worms and Pathogens, and Their Responses to Immunogenic Damage

  • Ashley B. Williams
  • Björn SchumacherEmail author


The nematode worm Caenorhabditis elegans has evolved a sophisticated innate immune response that responds to viral, bacterial, and fungal infections. Because of the lack of an adaptive immune response, including specialized immune cells, the worm has become a powerful model for studying highly conserved basic features of innate immune responses. In this chapter we discuss the signaling pathways that mediate the immune response and features of the worm’s defenses against specific pathogens, as they are currently understood. In particular, recent unique discoveries in C. elegans that have provided valuable details on the interconnectedness between innate immunity, organismal stress resistance, and longevity pathways are highlighted—particularly in the context of how a simple animal can respond to environmental assaults to preserve both its somatic tissue and genetic material.


Caenorhabditis elegans Innate immunity DNA damage MAP kinase Stress response Insulin signaling Toll-like receptor p38 signaling Viral defense RNA interference (RNAi) p53 tumor suppressor Surveillance immunity Cellular homeostasis 




Ortholog of phosphoinositide 3-kinase (PI3K) p110 catalytic subunit.


Homologs of serine/threonine kinase Akt/PKB ortholog of the serine/threonine kinase Akt/PKB.


Leucine zipper transcription factor; ortholog of CREB/activating transcription factors.


bZip transcription factor involved in UPRmt.


Ortholog of human CCAAT7 enhancer binding protein gamma (CEBPG).


BH3 domain-containing protein involved in apoptosis.


Ortholog of human tumor suppressor p53.


Receptor tyrosine kinase; insulin/insulin growth factor receptor ortholog.


Serine/threonine kinase; ortholog of type II transforming growth factor (TGF)-β receptor.


Forkhead box O (FOXO) transcription factor in insulin-mediated signaling.


Beta-type insulin; homologous to human insulin.


Member of transforming growth factor (TGF)-β super family.


Ortholog of human neuropeptide FF receptors (1 and 2) and pyroglutamylated RF amide peptide receptor.


Ribonuclease involved in RNA interference.


Dicer-related helicase involved in RNA interference.


BH3 domain-containing protein involved in apoptosis.


Ortholog of vertebrate RAF protein.


Mitogen-activated protein kinase (MAPK) kinase involved in Ras-mediated signaling.


Mitogen-activated protein kinase (MAPK); ortholog of human extracellular signal-regulated kinase (ERK).


RNaseD homolog involved in RNA interference.


G-protein-coupled neuropeptide receptor; homolog of mammalian neuropeptide Y receptor.


Neuronal symmetry family member 1. Mitogen-activated protein kinase (MAPK) kinase; ortholog of mammalian ASK family of proteins.


G-protein-coupled receptor involved in neuronal signaling.


Mitogen-activated protein kinase (MAPK); ortholog of human p38 MAPK, orthologous to human mi MAPK (OMIM:600289); MAPK, orthologous to human MAPK (OMIM:600289).


Argonaute and PIWI family protein.


Double-stranded RNA (dsRNA)-binding protein involved in RNA interference.


Ortholog of human mitogen-activated protein kinase kinases (MAPKK) 3 and 6.


Orthologs of SMAD proteins.


Serine/threonine protein kinase; orthologous to type I transforming growth factor (TGF)-β receptors.


Toll/interleukin-1 receptor domain adapter protein; ortholog of human SARM.


Toll-like receptor protein.


Mitochondrial unfolded protein response.


  1. Aballay A (2013) Role of the nervous system in the control of proteostasis during innate immune activation: insights from C. elegans. PLoS Pathog 9:e1003433. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Ahmed S, Hodgkin J (2000) MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans. Nature 403:159–164. CrossRefPubMedGoogle Scholar
  3. Ashe A, Bélicard T, Le Pen J, Sarkies P, Frézal L, Lehrbach NJ, Félix M-A, Miska EA (2013) A deletion polymorphism in the Caenorhabditis elegans RIG-I homolog disables viral RNA dicing and antiviral immunity. elife 2:e00994. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bolz DD, Tenor JL, Aballay A (2010) A conserved PMK-1/p38 MAPK is required in Caenorhabditis elegans tissue-specific immune response to Yersinia pestis infection. J Biol Chem 285:10832–10840. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Cezairliyan B, Vinayavekhin N, Grenfell-Lee D, Yuen GJ, Saghatelian A, Ausubel FM (2013) Identification of Pseudomonas aeruginosa phenazines that Kill Caenorhabditis elegans. PLoS Pathog 9:e1003101. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Chuang C-F, Bargmann CI (2004) A Toll-interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling. Genes Dev 19:270–281. CrossRefPubMedGoogle Scholar
  7. Coffman SR, Lu J, Guo X, Zhong J, Jiang H, Broitman-Maduro G, Li W-X, Lu R, Maduro M, Ding S-W (2017) Caenorhabditis elegans RIG-I homolog mediates antiviral RNA interference downstream of dicer-dependent biogenesis of viral small interfering RNAs. MBio 8:e00264–e00217. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Derry WB, Putzke AP, Rothman JH (2001) Caenorhabditis elegans p53: role in apoptosis, meiosis, and stress resistance. Science 294:591–595. CrossRefPubMedGoogle Scholar
  9. Dunbar TL, Yan Z, Balla KM, Smelkinson MG, Troemel ER (2012) C. elegans detects pathogen-induced translational inhibition to activate immune signaling. Cell Host Microbe 11:375–386. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Ermolaeva MA, Segref A, Dakhovnik A, Ou H-L, Schneider JI, Utermöhlen O, Hoppe T, Schumacher B (2013) DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature 501:416–420. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Estes KA, Dunbar TL, Powell JR, Ausubel FM, Troemel ER (2010) bZIP transcription factor zip-2 mediates an early response to Pseudomonas aeruginosa infection in Caenorhabditis elegans. Proc Natl Acad Sci U S A 107:2153–2158. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Félix M-A, Ashe A, Piffaretti J, Wu G, Nuez I, Bélicard T, Jiang Y, Zhao G, Franz CJ, Goldstein LD, Sanroman M, Miska EA, Wang D (2011) Natural and experimental infection of Caenorhabditis nematodes by novel viruses related to nodaviruses. PLoS Biol 9:e1000586. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Garsin DA, Villanueva JM, Begun J, Kim DH, Sifri CD, Calderwood SB, Ruvkun G, Ausubel FM (2003) Long-lived C. elegans daf-2 mutants are resistant to bacterial pathogens. Science 300:1921. CrossRefPubMedGoogle Scholar
  14. Gartner A, Milstein S, Ahmed S, Hodgkin J, Hengartner MO (2000) A conserved checkpoint pathway mediates DNA damage--induced apoptosis and cell cycle arrest in C. elegans. Mol Cell 5:435–443CrossRefGoogle Scholar
  15. Gravato-Nobre MJ, Nicholas HR, Nijland R, O'Rourke D, Whittington DE, Yook KJ, Hodgkin J (2005) Multiple genes affect sensitivity of Caenorhabditis elegans to the bacterial pathogen Microbacterium nematophilum. Genetics 171:1033–1045. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Guo X, Lu R (2013) Characterization of virus-encoded RNA interference suppressors in Caenorhabditis elegans. J Virol 87:5414–5423. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Guo X, Zhang R, Wang J, Ding S-W, Lu R (2013) Homologous RIG-I-like helicase proteins direct RNAi-mediated antiviral immunity in C. elegans by distinct mechanisms. Proc Natl Acad Sci U S A 110:16085–16090. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hodgkin J, Kuwabara PE, Corneliussen B (2000) A novel bacterial pathogen, Microbacterium nematophilum, induces morphological change in the nematode C. elegans. Curr Biol 10:1615–1618CrossRefGoogle Scholar
  19. Hofmann ER, Milstein S, Boulton SJ, Ye M, Hofmann JJ, Stergiou L, Gartner A, Vidal M, Hengartner MO (2002) Caenorhabditis elegans HUS-1 is a DNA damage checkpoint protein required for genome stability and EGL-1-mediated apoptosis. Curr Biol 12:1908–1918CrossRefGoogle Scholar
  20. Horst D, Verweij MC, Davison AJ, Ressing ME, Wiertz EJHJ (2011) Viral evasion of T cell immunity: ancient mechanisms offering new applications. Curr Opin Immunol 23:96–103. CrossRefPubMedGoogle Scholar
  21. Horvitz HR, Lecture N (2002) Worms, life and death. pp 320–351. CrossRefGoogle Scholar
  22. Hsin H, Kenyon C (1999) Signals from the reproductive system regulate the lifespan of C. Elegans. Nature 399(6734):362–366CrossRefGoogle Scholar
  23. Jansson HB (1994) Adhesion of conidia of Drechmeria coniospora to Caenorhabditis elegans wild type and mutants. J Nematol 26:430–435PubMedPubMedCentralGoogle Scholar
  24. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366:461–464. CrossRefPubMedGoogle Scholar
  25. Kim DH, Liberati NT, Mizuno T, Inoue H, Hisamoto N, Matsumoto K, Ausubel FM (2004) Integration of Caenorhabditis elegans MAPK pathways mediating immunity and stress resistance by MEK-1 MAPK kinase and VHP-1 MAPK phosphatase. Proc Natl Acad Sci U S A 101:10990–10994. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Kimble J, Crittenden SL (2005) Germline proliferation and its control. Worm Book 1–14.
  27. Kirienko NV, Ausubel FM, Ruvkun G (2015) Mitophagy confers resistance to siderophore-mediated killing by Pseudomonas aeruginosa. Proc Natl Acad Sci U S A 112:1821–1826. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kurz CL, Tan M-W (2004) Regulation of aging and innate immunity in C. elegans. Aging Cell 3:185–193. CrossRefPubMedGoogle Scholar
  29. Li W, Kennedy SG, Ruvkun G (2003) daf-28 encodes a C. elegans insulin superfamily member that is regulated by environmental cues and acts in the DAF-2 signaling pathway. Genes Dev 17:844–858. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Liberati NT, Fitzgerald KA, Kim DH, Feinbaum R, Golenbock DT, Ausubel FM (2004) Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response. Proc Natl Acad Sci U S A 101:6593–6598. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Libina N, Berman JR, Kenyon C (2003) Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell 115:489–502CrossRefGoogle Scholar
  32. Lin K, Hsin H, Libina N, Kenyon C (2001) Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 28:139–145CrossRefGoogle Scholar
  33. Liu Y, Samuel BS, Breen PC, Ruvkun G (2014) Caenorhabditis elegans pathways that surveil and defend mitochondria. Nature 508:406–410. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Mahajan-Miklos S, Tan MW, Rahme LG, Ausubel FM (1999) Molecular mechanisms of bacterial virulence elucidated using a Pseudomonas aeruginosa-Caenorhabditis elegans pathogenesis model. Cell 96:47–56CrossRefGoogle Scholar
  35. Mallo GV, Kurz CL, Couillault C, Pujol N, Granjeaud S, Kohara Y, Ewbank JJ (2002) Inducible antibacterial defense system in C. elegans. Curr Biol 12:1209–1214CrossRefGoogle Scholar
  36. Malone EA, Inoue T, Thomas JH (1996) Genetic analysis of the roles of daf-28 and age-1 in regulating Caenorhabditis elegans dauer formation. Genetics 143:1193–1205. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Marsh EK, May RC (2012) Caenorhabditis elegans, a model organism for investigating immunity. Appl Environ Microbiol 78:2075–2081. CrossRefPubMedPubMedCentralGoogle Scholar
  38. McEwan DL, Kirienko NV, Ausubel FM (2012) Host translational inhibition by Pseudomonas aeruginosa Exotoxin A Triggers an immune response in Caenorhabditis elegans. Cell Host Microbe 11:364–374. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Miller EV, Grandi LN, Giannini JA, Robinson JD, Powell JR (2015) The conserved G-protein coupled receptor FSHR-1 regulates protective host responses to infection and oxidative stress. PLoS One 10:e0137403–e0137416. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Nargund AM, Pellegrino MW, Fiorese CJ, Baker BM, Haynes CM (2012) Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337:587–590. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Nicholas HR, Hodgkin J (2004) The ERK MAP kinase cascade mediates tail swelling and a protective response to rectal infection in C. elegans. Curr Biol 14:1256–1261. CrossRefPubMedGoogle Scholar
  42. Nougayrede JP, Homburg S, Taieb F, Boury M, Brzuszkiewicz E, Gottschalk G, Buchrieser C, Hacker J, Dobrindt U, Oswald E (2006) Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science 313:848–851. CrossRefPubMedGoogle Scholar
  43. Paradis S, Ruvkun G (1998) Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev 12:2488–2498. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Pees B, Kloock A, Nakad R, Barbosa C, Dierking K (2017) Enhanced behavioral immune defenses in a C. elegans C-type lectin-like domain gene mutant. Dev Comp Immunol 74:237–242. CrossRefPubMedGoogle Scholar
  45. Pellegrino MW, Nargund AM, Kirienko NV, Gillis R, Fiorese CJ, Haynes CM (2014) Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature 516:414–417. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Powell JR, Kim DH, Ausubel FM (2009) The G protein-coupled receptor FSHR-1 is required for the Caenorhabditis elegans innate immune response. Proc Natl Acad Sci U S A 106:2782–2787. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Pujol N, Link EM, Liu LX, Kurz CL, Alloing G, Tan MW, Ray KP, Solari R, Johnson CD, Ewbank JJ (2001) A reverse genetic analysis of components of the toll signaling pathway in Caenorhabditis elegans. Curr Biol 11:809–821CrossRefGoogle Scholar
  48. Pukkila-Worley R (2016) Surveillance immunity: an emerging paradigm of innate defense activation in Caenorhabditis elegans. PLoS Pathog 12:e1005795–e1005795. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Reddy KC, Andersen EC, Kruglyak L, Kim DH (2009) A polymorphism in npr-1 is a behavioral determinant of pathogen susceptibility in C. elegans. Science 323:382–384. CrossRefPubMedPubMedCentralGoogle Scholar
  50. Reddy KC, Dunbar TL, Nargund AM, Haynes CM, Troemel ER (2016) The C. elegans CCAAT-enhancer-binding protein gamma is required for surveillance. Immunity 14:1581–1589. CrossRefGoogle Scholar
  51. Roberts AF, Gumienny TL, Gleason RJ, Wang H, Padgett RW (2010) Regulation of genes affecting body size and innate immunity by the DBL-1/BMP-like pathway in Caenorhabditis elegans. BMC Dev Biol 10:61. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Schumacher B, Hofmann K, Boulton S, Gartner A (2001) The C. elegans homolog of the p53 tumor suppressor is required for DNA damage-induced apoptosis. Curr Biol 11:1722–1727CrossRefGoogle Scholar
  53. Schumacher B, Schertel C, Wittenburg N, Tuck S, Mitani S, Gartner A, Conradt B, Shaham S (2005) C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage. Cell Death Differ 12:153–161CrossRefGoogle Scholar
  54. Shivers RP, Pagano DJ, Kooistra T, Richardson CE, Reddy KC, Whitney JK, Kamanzi O, Matsumoto K, Hisamoto N, Kim DH (2010) Phosphorylation of the conserved transcription factor ATF-7 by PMK-1 p38 MAPK regulates innate immunity in Caenorhabditis elegans. PLoS Genet 6:e1000892. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Shivers RP, Youngman MJ, Kim DH (2008) Transcriptional responses to pathogens in Caenorhabditis elegans. Curr Opin Microbiol 11:251–256. CrossRefPubMedPubMedCentralGoogle Scholar
  56. Styer KL, Singh V, Macosko E, Steele SE, Bargmann CI, Aballay A (2008) Innate immunity in Caenorhabditis elegans is regulated by neurons expressing NPR-1/GPCR. Science 322:460–464. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Sun J, Singh V, Kajino-Sakamoto R, Aballay A (2011) Neuronal GPCR controls innate immunity by regulating noncanonical unfolded protein response genes. Science 332:729–732. CrossRefPubMedPubMedCentralGoogle Scholar
  58. Tazearslan Ç, Ayyadevara S, Bharill P, Reis RJS (2009) Positive feedback between transcriptional and kinase suppression in nematodes with extraordinary longevity and stress resistance. PLoS Genet 5:e1000452. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Tenor JL, Aballay A (2007) A conserved Toll-like receptor is required for Caenorhabditis elegans innate immunity. EMBO Rep 9:103–109. CrossRefPubMedPubMedCentralGoogle Scholar
  60. Toller IM, Neelsen KJ, Steger M, Hartung ML, Hottiger MO, Stucki M, Kalali B, Gerhard M, Sartori AA, Lopes M, Muller A (2011) Carcinogenic bacterial pathogen Helicobacter pylori triggers DNA double-strand breaks and a DNA damage response in its host cells. Proc Natl Acad Sci U S A 108:14944–14949. CrossRefPubMedPubMedCentralGoogle Scholar
  61. Troemel ER, Chu SW, Reinke V, Lee SS, Ausubel FM, Kim DH (2006) p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans. PLoS Genet 2:e183. CrossRefPubMedPubMedCentralGoogle Scholar
  62. Zugasti O, Bose N, Squiban B, Belougne JEROM, Kurz CLEO, Schroeder FC, Pujol N, Ewbank JJ (2014) Activation of a G protein–coupled receptor by its endogenous ligand triggers the innate immune response of Caenorhabditis elegans. Nat Immunol 15:833–838. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute for Genome Stability in Aging and Disease, Medical Faculty, University of CologneCologneGermany
  2. 2.Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of CologneCologneGermany
  3. 3.Center for Molecular Medicine (CMMC), University of CologneCologneGermany

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