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:

TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM

Nature Immunology volume 5, pages 488–494 (2004)Cite this article

Abstract

Both plants and animals respond to infection by synthesizing compounds that directly inhibit or kill invading pathogens. We report here the identification of infection-inducible antimicrobial peptides in Caenorhabditis elegans. Expression of two of these peptides, NLP-29 and NLP-31, was differentially regulated by fungal and bacterial infection and was controlled in part by tir-1, which encodes an ortholog of SARM, a Toll–interleukin 1 receptor (TIR) domain protein. Inactivation of tir-1 by RNA interference caused increased susceptibility to infection. We identify protein partners for TIR-1 and show that the small GTPase Rab1 and the f subunit of ATP synthase participate specifically in the control of antimicrobial peptide gene expression. As the activity of tir-1 was independent of the single nematode Toll-like receptor, TIR-1 may represent a component of a previously uncharacterized, but conserved, innate immune signaling pathway.

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: Infection-induced peptides are members of conserved families.
Figure 2: NLP-31 has an in vitro antifungal effect.
Figure 3: Infection upregulates the expression of pnlp:gfp reporter genes.
Figure 4: The tir-1 gene controls pnlp::gfp reporter gene expression in a TLR-independent way.
Figure 5: The gene tir-1 is required for the resistance of C. elegans to infection.
Figure 6: Both rab-1 and R53.4 influence nlp-29::gfp reporter gene expression.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Khush, R.S. & Lemaitre, B. Genes that fight infection: what the Drosophila genome says about animal immunity. Trends Genet. 16, 442– 449 (2000).

    Article  CAS  Google Scholar 

  3. Hoffmann, J.A. & Reichhart, J.M. Drosophila innate immunity: an evolutionary perspective. Nat. Immunol. 3, 121– 126 (2002).

    Article  CAS  Google Scholar 

  4. 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 

  5. De Gregorio, E., Spellman, P.T., Tzou, P., Rubin, G.M. & Lemaitre, B. The Toll and Imd pathways are the major regulators of the immune response in Drosophila . EMBO J. 21, 2568– 2579 (2002).

    Article  CAS  Google Scholar 

  6. 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 

  7. Imler, J.L. & Hoffmann, J.A. Toll receptors in Drosophila: a family of molecules regulating development and immunity. Curr. Top. Microbiol. Immunol. 270, 63– 79 (2002).

    CAS  PubMed  Google Scholar 

  8. Jebanathirajah, J.A., Peri, S. & Pandey, A. Toll and interleukin-1 receptor (TIR) domain-containing proteins in plants: a genomic perspective. Trends Plant Sci. 7, 388– 391 (2002).

    Article  CAS  Google Scholar 

  9. Bilak, H., Tauszig-Delamasure, S. & Imler, J.-L. Toll and Toll-like receptors in Drosophila . Biochem. Soc. Trans. 31, 647– 650 (2003).

    Article  Google Scholar 

  10. Ooi, J.Y., Yagi, Y., Hu, X. & Ip, Y.T. The Drosophila Toll-9 activates a constitutive antimicrobial defense. EMBO Rep. 3, 82– 87 (2002).

    Article  CAS  Google Scholar 

  11. Tauszig-Delamasure, S., Bilak, H., Capovilla, M., Hoffmann, J.A. & Imler, J.L. Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections. Nat. Immunol. 3, 91– 97 (2002).

    Article  CAS  Google Scholar 

  12. Fitzgerald, K.A. et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413, 78– 83 (2001).

    Article  CAS  Google Scholar 

  13. Horng, T., Barton, G.M., Flavell, R.A. & Medzhitov, R. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420, 329– 333 (2002).

    Article  CAS  Google Scholar 

  14. Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T. & Seya, T. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-β induction. Nat. Immunol. 4, 161– 167 (2003).

    Article  CAS  Google Scholar 

  15. Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640– 643 (2003).

    Article  CAS  Google Scholar 

  16. Hoebe, K. et al. Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways. Nat. Immunol. 4, 1223– 1229 (2003).

    Article  CAS  Google Scholar 

  17. Yamamoto, M. et al. TRAM is specifically involved in the Toll-like receptor 4–mediated MyD88-independent signaling pathway. Nat. Immunol. 4, 1144– 1150 (2003).

    Article  CAS  Google Scholar 

  18. Mink, M., Fogelgren, B., Olszewski, K., Maroy, P. & Csiszar, K. A novel human gene (SARM) at chromosome 17q11 encodes a protein with a SAM motif and structural similarity to Armadillo/β-catenin that is conserved in mouse, Drosophila, and Caenorhabditis elegans . Genomics 74, 234– 244 (2001).

    Article  CAS  Google Scholar 

  19. O'Neill, L.A., Fitzgerald, K.A. & Bowie, A.G. The Toll-IL-1 receptor adaptor family grows to five members. Trends Immunol. 24, 286– 290 (2003).

    Article  Google Scholar 

  20. Kurz, C.L. & Ewbank, J.J. Caenorhabditis elegans: an emerging genetic model for the study of innate immunity. Nat. Rev. Genet. 4, 380– 390 (2003).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Millet, A.C.M. & Ewbank, J.J. Immunity in Caenorhabditis elegans . Curr. Opin. Immunol. 16, 4– 9 (2004).

    Article  CAS  Google Scholar 

  25. Jansson, H.B. Adhesion of conidia of Drechmeria coniospora to Caenorhabditis elegans wild type and mutants. J. Nematol. 26, 430– 435 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Kurz, C.L. et al. Virulence factors of the human opportunistic pathogen Serratia marcescens identified by in vivo screening. EMBO J. 22, 1451– 1460 (2003).

    Article  CAS  Google Scholar 

  28. Nathoo, A.N., Moeller, R.A., Westlund, B.A. & Hart, A.C. Identification of neuropeptide-like protein gene families in Caenorhabditis elegans and other species. Proc. Natl. Acad. Sci. USA 98, 14000– 14005 (2001).

    Article  CAS  Google Scholar 

  29. Ehret-Sabatier, L. et al. Characterization of novel cysteine-rich antimicrobial peptides from scorpion blood. J. Biol. Chem. 271, 29537– 29544 (1996).

    Article  CAS  Google Scholar 

  30. Kato, Y. et al. abf-1 and abf-2, ASABF-type antimicrobial peptide genes in Caenorhabditis elegans . Biochem. J. 361, 221– 230 (2002).

    Article  CAS  Google Scholar 

  31. 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  Google Scholar 

  32. 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  Google Scholar 

  33. Beutler, B. & Rehli, M. Evolution of the TIR, tolls and TLRs: functional inferences from computational biology. Curr. Top. Microbiol. Immunol. 270, 1– 21 (2002).

    CAS  PubMed  Google Scholar 

  34. Harris, T.W. et al. WormBase: a cross-species database for comparative genomics. Nucleic Acids Res. 31, 133– 137 (2003).

    Article  CAS  Google Scholar 

  35. Timmons, L. & Fire, A. Specific interference by ingested dsRNA. Nature 395, 854 (1998).

    Article  CAS  Google Scholar 

  36. Kamath, R.S. et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421, 231– 237 (2003).

    Article  CAS  Google Scholar 

  37. Lambert, R.W., Campton, K., Ding, W., Ozawa, H. & Granstein, R.D. Langerhans cell expression of neuropeptide Y and peptide YY. Neuropeptides 36, 246– 251 (2002).

    Article  CAS  Google Scholar 

  38. Vouldoukis, I., Shai, Y., Nicolas, P. & Mor, A. Broad spectrum antibiotic activity of the skin-PYY. FEBS Lett. 380, 237– 240 (1996).

    Article  CAS  Google Scholar 

  39. Metz-Boutigue, M.H., Kieffer, A.E., Goumon, Y. & Aunis, D. Innate immunity: involvement of new neuropeptides. Trends Microbiol. 11, 585– 592 (2003).

    Article  CAS  Google Scholar 

  40. Tzou, P., Reichhart, J.M. & Lemaitre, B. Constitutive expression of a single antimicrobial peptide can restore wild-type resistance to infection in immunodeficient Drosophila mutants. Proc. Natl. Acad. Sci. USA 99, 2152– 2157 (2002).

    Article  CAS  Google Scholar 

  41. Nielsen, H., Engelbrecht, J., Brunak, S. & von Heijne, G. A neural network method for identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites. Int. J. Neural Syst. 8, 581– 599 (1997).

    Article  CAS  Google Scholar 

  42. Mello, C.C., Kramer, J.M., Stinchcomb, D. & Ambros, V. Efficient gene transfer in C. elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J. 10, 3959– 3970 (1991).

    Article  CAS  Google Scholar 

  43. Bertucci, F. et al. Sensitivity issues in DNA array-based expression measurements and performance of nylon microarrays for small samples. Hum. Mol. Genet. 8, 1715– 1722 (1999).

    Article  CAS  Google Scholar 

  44. Kamath, R.S., Martinez-Campos, M., Zipperlen, P., Fraser, A.G. & Ahringer, J. Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans . Genome Biol. 2, research 0002.1– 0002.10 (2001).

    Google Scholar 

  45. Walhout, A.J. et al. Protein interaction mapping in C. elegans using proteins involved in vulval development. Science 287, 116– 122 (2000).

    Article  CAS  Google Scholar 

  46. 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  Google Scholar 

  47. Vaglio, P. et al. WorfDB: the Caenorhabditis elegans ORFeome Database. Nucleic Acids Res. 31, 237– 240 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Some strains were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health National Center for Research Resources. Certain RNAi bacterial strains were from the Ahringer library provided by MRC geneservice. Mass spectroscopy was done with the facilities of the Proteomic Platform of the Montpellier-Languedoc-Roussillon genopole, microarray, and worm sorting analyses, with those of the Transcriptome and C. elegans functional genomics Platforms of the Marseille-Nice genopole. We thank A. Blanc and N. O'Neill for advice on sorting; J.-L. Bessereau, A. Fire and A. Hart for the gift of vectors; A. Coulson and the Worm Genome Research Consortium for providing the clones and sequences that made this work possible; H.-B. Jansson for the gift of drechmeria; S. Granjeaud and B. Loriod for assistance with the microarray experiments; E. De Gregorio, C. Hetru, J.L. Imler and L. Troxler for communicating results before publication and/or discussion; and P. Golstein and T. Lecuit for critical reading of the manuscript. Supported by institutional grants from the Centre National de la Recherche Scientifique and Institut National de la Santé et de la Recherche Médicale, Ministry of Research (Programme de Recherche Fondamentale en Microbiologie et Maladies Infectieuses et Parasitaires and Action Concertée Incitative-Biologie du Développement et Physiologie Intégrative) and Centre National de la Recherche Scientifique (Actions Thématiques et Incitatives sur Programme et Equipes) grants to J.J.E.

Author information

Authors and Affiliations

  1. Centre d'Immunologie de Marseille-Luminy, Institut National de la Santé et de la Recherche Médicale/Centre National de la Recherche Scientifique/Université de la Méditerranée, Case 906, Marseille, 13288, Cedex 9, France

    Carole Couillault, Nathalie Pujol & Jonathan J Ewbank

  2. Institut National de la Santé et de la Recherche Médicale U119, Institut Paoli Calmette, Marseille, 13009, France

    Jérôme Reboul

  3. Institut de Biologie Moléculaire et Cellulaire, UPR 9022, Centre National de la Recherche Scientifique, 15 rue Descartes, Strasbourg, 67084, Cedex, France

    Laurence Sabatier

  4. Centre de Biochimie Structurale, Centre National de la Recherche Scientifique UMR 5048, Institut National de la Santé et de la Recherche Médicale UMR 554, Université de Montpellier 1, 29, rue de Navacelles, Montpellier, 34090, Cedex, France

    Jean-François Guichou

  5. National Institute of Genetics, Mishima, 411, Japan

    Yuji Kohara

Authors
  1. Carole Couillault
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nathalie Pujol
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jérôme Reboul
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laurence Sabatier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean-François Guichou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuji Kohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jonathan J Ewbank
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonathan J Ewbank.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Couillault, C., Pujol, N., Reboul, J. 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). https://doi.org/10.1038/ni1060

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1060

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