Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Neuroimmune regulation of antimicrobial peptide expression by a noncanonical TGF-β signaling pathway in Caenorhabditis elegans epidermis

Nature Immunology volume 10, pages 249–256 (2009)Cite this article

Abstract

After being infected by the fungus Drechmeria coniospora, Caenorhabditis elegans produces antimicrobial peptides in its epidermis, some regulated by a signaling cascade involving a p38 mitogen-activated protein kinase. Here we show that infection-induced expression of peptides of the Caenacin family occurred independently of the p38 pathway. The caenacin (cnc) genes enhanced survival after fungal infection, and neuronal expression of the transforming growth factor-β homolog DBL-1 promoted cnc-2 expression in the epidermis in a dose-dependent paracrine way. Our results lead to a model in which antifungal defenses are coordinately regulated by a cell-autonomous p38 cascade and a distinct cytokine-like transforming growth factor-β signal from the nervous system, each of which controls distinct sets of antimicrobial peptide–encoding genes in the epidermis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Expression of genes in the cnc-2 cluster.
Figure 2: Overexpression of the cnc-2 cluster is associated with greater resistance to infection.
Figure 3: D. coniospora infection specifically induces expression of the cnc-2 reporter.
Figure 4: Upregulation of pcnc-2::GFP after fungal infection requires dbl-1.
Figure 5: Upregulation of pcnc-2::GFP after fungal infection requires sma-6 and daf-4.
Figure 6: Upregulation of cnc-2 after infection does not require sma-2 or sma-4.
Figure 7: Influence of dbl-1 expression on cnc-2 upregulation.
Figure 8: Neuronal expression of dbl-1 is sufficient to restore body size (length) and upregulation of the cnc-2 reporter after fungal infection in dbl-1-mutant worms.

Similar content being viewed by others

References

  1. Tan, M.W. & Ausubel, F.M. Caenorhabditis elegans: a model genetic host to study Pseudomonas aeruginosa pathogenesis. Curr. Opin. Microbiol. 3, 29–34 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Ewbank, J.J. Tackling both sides of the host-pathogen equation with Caenorhabditis elegans. Microbes Infect. 4, 247–256 (2002).

    Article  PubMed  Google Scholar 

  3. Sifri, C.D., Begun, J. & Ausubel, F.M. The worm has turned–microbial virulence modeled in Caenorhabditis elegans. Trends Microbiol. 13, 119–127 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Gravato-Nobre, M.J. & Hodgkin, J. Caenorhabditis elegans as a model for innate immunity to pathogens. Cell. Microbiol. 7, 741–751 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Zhang, Y. Neuronal mechanisms of Caenorhabditis elegans and pathogenic bacteria interactions. Curr. Opin. Microbiol. 11, 257–261 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Schulenburg, H. & Ewbank, J.J. The genetics of pathogen avoidance in Caenorhabditis elegans. Mol. Microbiol. 66, 563–570 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Shivers, R.P., Youngman, M.J. & Kim, D.H. Transcriptional responses to pathogens in Caenorhabditis elegans. Curr. Opin. Microbiol. 11, 251–256 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schulenburg, H., Kurz, C.L. & Ewbank, J.J. Evolution of the innate immune system: the worm perspective. Immunol. Rev. 198, 36–58 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Nicholas, H.R. & Hodgkin, J. Responses to infection and possible recognition strategies in the innate immune system of Caenorhabditis elegans. Mol. Immunol. 41, 479–493 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Pujol, N. et al. A reverse genetic analysis of components of the Toll signalling pathway in Caenorhabditis elegans. Curr. Biol. 11, 809–821 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Pradel, E. et al. Detection and avoidance of a natural product from the pathogenic bacterium Serratia marcescens by Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 104, 2295–2300 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tenor, J.L. & Aballay, A. A conserved Toll-like receptor is required for Caenorhabditis elegans innate immunity. EMBO Rep. 9, 103–109 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Haskins, K.A., Russell, J.F., Gaddis, N., Dressman, H.K. & Aballay, A. Unfolded protein response genes regulated by CED-1 are required for Caenorhabditis elegans innate immunity. Dev. Cell 15, 87–97 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Couillault, C. et al. TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nat. Immunol. 5, 488–494 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Pujol, N. et al. Distinct innate immune responses to infection and wounding in the C. elegans epidermis. Curr. Biol. 18, 481–489 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pujol, N. et al. Anti-fungal innate immunity in C. elegans is enhanced by evolutionary diversification of antimicrobial peptides. PLoS Pathog. 4, e1000105 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Dijksterhuis, J., Veenhuis, M. & Harder, W. Ultrastructural study of adhesion and initial stages of infection of the nematode by conidia of Drechmeria coniospora. Mycol. Res. 94, 1–8 (1990).

    Article  Google Scholar 

  18. Nicholas, H.R. & Hodgkin, J. The ERK MAP kinase cascade mediates tail swelling and a protective response to rectal infection in C. elegans. Curr. Biol. 14, 1256–1261 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Mallo, G.V. et al. Inducible antibacterial defense system in C. elegans. Curr. Biol. 12, 1209–1214 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Tan, M.W. Genetic and genomic dissection of host-pathogen interactions using a P. aeruginosa-C. elegans pathogenesis model. Pediatr. Pulmonol. 32, 96–97 (2001).

    Google Scholar 

  21. Morita, K., Chow, K.L. & Ueno, N. Regulation of body length and male tail ray pattern formation of Caenorhabditis elegans by a member of TGF-beta family. Development 126, 1337–1347 (1999).

    CAS  PubMed  Google Scholar 

  22. Suzuki, Y. et al. A BMP homolog acts as a dose-dependent regulator of body size and male tail patterning in Caenorhabditis elegans. Development 126, 241–250 (1999).

    CAS  PubMed  Google Scholar 

  23. Savage, C. et al. Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor beta pathway components. Proc. Natl. Acad. Sci. USA 93, 790–794 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Savage-Dunn, C. TGF-β signaling. WormBook (ed. The C. elegans Research Community) doi/10.1895/wormbook.1.22.1 (9 September 2005).

    Google Scholar 

  25. Schmierer, B. & Hill, C.S. TGFβ-SMAD signal transduction: molecular specificity and functional flexibility. Nat. Rev. Mol. Cell Biol. 8, 970–982 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Reboul, J. et al. C. elegans ORFeome version 1.1: experimental verification of the genome annotation and resource for proteome-scale protein expression. Nat. Genet. 34, 35–41 (2003).

    Article  PubMed  Google Scholar 

  27. Watanabe, N., Ishihara, T. & Ohshima, Y. Mutants carrying two sma mutations are super small in the nematode C. elegans. Genes Cells 12, 603–609 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Savage-Dunn, C. et al. Genetic screen for small body size mutants in C. elegans reveals many TGFβ pathway components. Genesis 35, 239–247 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Gumienny, T.L. et al. Glypican LON-2 is a conserved negative regulator of BMP-like signaling in Caenorhabditis elegans. Curr. Biol. 17, 159–164 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Mochii, M., Yoshida, S., Morita, K., Kohara, Y. & Ueno, N. Identification of transforming growth factor-β-regulated genes in Caenorhabditis elegans by differential hybridization of arrayed cDNAs. Proc. Natl. Acad. Sci. USA 96, 15020–15025 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  32. Imler, J.L. & Bulet, P. Antimicrobial peptides in Drosophila: structures, activities and gene regulation. Chem. Immunol. Allergy 86, 1–21 (2005).

    CAS  PubMed  Google Scholar 

  33. Fehlbaum, P. et al. Insect immunity. Septic injury of Drosophila induces the synthesis of a potent antifungal peptide with sequence homology to plant antifungal peptides. J. Biol. Chem. 269, 33159–33163 (1994).

    CAS  PubMed  Google Scholar 

  34. Murray-Rust, J. et al. Topological similarities in TGF-β2, PDGF-BB and NGF define a superfamily of polypeptide growth factors. Structure 1, 153–159 (1993).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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  PubMed  PubMed Central  Google Scholar 

  38. Jang, I.H. et al. A Spatzle-processing enzyme required for toll signaling activation in Drosophila innate immunity. Dev. Cell 10, 45–55 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Schwartz, M.A. & Madhani, H.D. Principles of MAP kinase signaling specificity in Saccharomyces cerevisiae. Annu. Rev. Genet. 38, 725–748 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Chuang, C.F. & Bargmann, C.I.A. Toll-interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling. Genes Dev. 19, 270–281 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kim, D.H. et al. A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. Science 297, 623–626 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Kurz, C.L. & Tan, M.W. Regulation of aging and innate immunity in C. elegans. Aging Cell 3, 185–193 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Kawli, T. & Tan, M.W. Neuroendocrine signals modulate the innate immunity of Caenorhabditis elegans through insulin signaling. Nat. Immunol. 9, 1415–1424 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Liang, B., Moussaif, M., Kuan, C.J., Gargus, J.J. & Sze, J.Y. Serotonin targets the DAF-16/FOXO signaling pathway to modulate stress responses. Cell Metab. 4, 429–440 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Reddy, K.C., Andersen, E.C., Kruglyak, L. & Kim, D.H. A polymorphism in npr-1 is a behavioral determinant of pathogen susceptibility in. C. elegans. Science 323, 382–384 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Baumeister, R., Schaffitzel, E. & Hertweck, M. Endocrine signaling in Caenorhabditis elegans controls stress response and longevity. J. Endocrinol. 190, 191–202 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Evans, E.A., Kawli, T. & Tan, M.W. Pseudomonas aeruginosa suppresses host immunity by activating the DAF-2 insulin-like signaling pathway in Caenorhabditis elegans. PLoS Pathog. 4, e1000175 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Apidianakis, Y. et al. Profiling early infection responses: Pseudomonas aeruginosa eludes host defenses by suppressing antimicrobial peptide gene expression. Proc. Natl. Acad. Sci. USA 102, 2573–2578 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chamilos, G. et al. Drosophila melanogaster as a model host to dissect the immunopathogenesis of zygomycosis. Proc. Natl. Acad. Sci. USA 105, 9367–9372 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Timmons, L., Court, D.L. & Fire, A. Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans. Gene 263, 103–112 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank A. Chisholm, P. Golstein, J. Hodgkin, J.-L. Imler and members of the Ewbank laboratory for discussion and comments on the manuscript, and R.W. Padgett (Rutgers University) for the wt;ctIs40 strain; some other nematode strains were provided by the Caenorhabditis Genetics Center (funded by the National Institutes of Health National Center for Research Resources) or by the National Bioresource Project coordinated by S. Mitani (Tokyo Women's Medical University School of Medicine). Worm sorter analyses were done in the facilities of Marseille-Nice Genopole. Supported by the Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, the Agence National de Recherches (Droselegans, Fungenomics) and Union Biometrica. The Ewbank lab is an Équipe Labellisée Fondation pour la Recherche Médicale.

Author information

Authors and Affiliations

  1. Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Case 906, Marseille cedex 9, 13288, France

    Olivier Zugasti & Jonathan J Ewbank

  2. Institut National de la Santé et de la Recherche Médicale U631, Marseille, 13288, France

    Olivier Zugasti & Jonathan J Ewbank

  3. Centre National de la Recherche Scientifique UMR6102, Marseille, 13288, France

    Olivier Zugasti & Jonathan J Ewbank

Authors
  1. Olivier Zugasti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jonathan J Ewbank
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

O.Z. and J.J.E. designed the experiments, interpreted the data and wrote the manuscript, and O.Z. did the experimental studies.

Corresponding author

Correspondence to Jonathan J Ewbank.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–13, Table 1 and Supplementary Methods (PDF 7295 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zugasti, O., Ewbank, J. Neuroimmune regulation of antimicrobial peptide expression by a noncanonical TGF-β signaling pathway in Caenorhabditis elegans epidermis. Nat Immunol 10, 249–256 (2009). https://doi.org/10.1038/ni.1700

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1700

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing