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.

The Drosophila immune response against Gram-negative bacteria is mediated by a peptidoglycan recognition protein

Abstract

The antimicrobial defence of Drosophila relies largely on the challenge-induced synthesis of an array of potent antimicrobial peptides by the fat body1,2. The defence against Gram-positive bacteria and natural fungal infections is mediated by the Toll signalling pathway, whereas defence against Gram-negative bacteria is dependent on the Immune deficiency (IMD) pathway3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18. Loss-of-function mutations in either pathway reduce the resistance to corresponding infections3,9. The link between microbial infections and activation of these two pathways has remained elusive. The Toll pathway is activated by Gram-positive bacteria through a circulating Peptidoglycan recognition protein (PGRP-SA)6. PGRPs appear to be highly conserved from insects to mammals, and the Drosophila genome contains 13 members19,20,21,22,23. Here we report a mutation in a gene coding for a putative transmembrane protein, PGRP-LC, which reduces survival to Gram-negative sepsis but has no effect on the response to Gram-positive bacteria or natural fungal infections. By genetic epistasis, we demonstrate that PGRP-LC acts upstream of the imd gene. The data on PGRP-SA with respect to the response to Gram-positive infections, together with the present report, indicate that the PGRP family has a principal role in sensing microbial infections in Drosophila.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Schematic representation of the PGRP-LC locus.
Figure 2: Expression of antimicrobial peptides in different mutant backgrounds after infection by Gram-negative bacteria, Gram-positive bacteria or fungi.
Figure 3: PGRP-LC mutant flies are highly susceptible to infection by Gram-negative bacteria.
Figure 4: PGRP-LC is genetically upstream of imd.

References

  1. 1

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

    CAS  Article  Google Scholar 

  2. 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)

    CAS  Article  Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

    Meng, X., Khanuja, B. S. & Ip, Y. T. Toll receptor-mediated Drosophila immune response requires Dif, an NF-κB factor. Genes Dev. 13, 792–797 (1999)

    CAS  Article  Google Scholar 

  5. 5

    Rutschmann, S. et al. The Rel protein DIF mediates the antifungal, but not the antibacterial, response in Drosophila. Immunity 12, 569–580 (2000)

    CAS  Article  Google Scholar 

  6. 6

    Michel, T., Reichhart, J., Hoffmann, J. A. & Royet, J. Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein. Nature 414, 756–759 (2001)

    ADS  CAS  Article  Google Scholar 

  7. 7

    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. Nature Immunol. 3, 91–97 (2002)

    CAS  Article  Google Scholar 

  8. 8

    Rutschmann, S., Kilinc, A. & Ferrandon, D. The Toll pathway is required for resistance to Gram-positive bacterial infections in Drosophila. J. Immunol. 168, 1542–1546 (2002)

    CAS  Article  Google Scholar 

  9. 9

    Lemaitre, B. et al. A recessive mutation, immune deficiency (imd), defines two distinct control pathways in the Drosophila host defence. Proc. Natl Acad. Sci. USA 92, 9465–9469 (1995)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Hedengren, M. et al. Relish, a central factor in the control of humoral but not cellular immunity in Drosophila. Mol. Cell 4, 1–20 (1999)

    Article  Google Scholar 

  11. 11

    Elrod-Erickson, M., Mishra, S. & Schneider, D. Interactions between the cellular and humoral immune responses in Drosophila. Curr. Biol. 10, 781–784 (2000)

    CAS  Article  Google Scholar 

  12. 12

    Rutschmann, S. et al. Role of Drosophila IKKγ in a Toll-independent antibacterial immune response. Nature Immunol. 1, 342–347 (2000)

    CAS  Article  Google Scholar 

  13. 13

    Silverman, N. et al. A Drosophila IκB kinase complex required for Relish cleavage and antibacterial immunity. Genes Dev. 14, 2461–2471 (2000)

    CAS  Article  Google Scholar 

  14. 14

    Leulier, F., Rodriguez, A., Khush, R. S., Abrams, J. M. & Lemaitre, B. The Drosophila caspase Dredd is required to resist Gram-negative bacterial infections. EMBO Rep. 1, 353–358 (2000)

    CAS  Article  Google Scholar 

  15. 15

    Lu, Y., Wu, L. P. & Anderson, K. V. The antibacterial arm of the Drosophila innate immune response requires an IκB kinase. Genes Dev. 15, 104–110 (2001)

    CAS  Article  Google Scholar 

  16. 16

    Vidal, S. et al. Mutations in the Drosophila dTAK1 gene reveal a conserved function for MAPKKKs in the control of rel/NF-κB dependent innate immune responses. Genes Dev. 15, 1900–1912 (2001)

    CAS  Article  Google Scholar 

  17. 17

    Wu, L. P., Choe, K. M., Lu, Y. & Anderson, K. V. Drosophila immunity: genes on the third chromosome required for the response to bacterial infection. Genetics 159, 189–199 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Georgel, P. et al. Drosophila Immune Deficiency (IMD) is a Death Domain protein that activates antibacterial defense and can promote apoptosis. Dev. Cell 1, 503–514 (2001)

    CAS  Article  Google Scholar 

  19. 19

    Yoshida, H., Kinoshita, K. & Ashida, M. Purification of a peptidoglycan recognition protein from hemolymph of the silkworm, Bombyx mori. J. Biol. Chem. 271, 13854–13860 (1996)

    CAS  Article  Google Scholar 

  20. 20

    Kang, D., Liu, G., Lundstrom, A., Gelius, E. & Steiner, H. A peptidoglycan recognition protein in innate immunity conserved from insects to humans. Proc. Natl Acad. Sci. USA 95, 10078–10082 (1998)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Werner, T. et al. A family of peptidoglycan recognition proteins in the fruit fly Drosophila melanogaster. Proc. Natl Acad. Sci. USA 97, 13772–13777 (2000)

    ADS  CAS  Article  Google Scholar 

  22. 22

    Liu, C., Gelius, E., Liu, G., Steiner, H. & Dziarski, R. Mammalian peptidoglycan recognition protein binds peptidoglycan with high affinity, is expressed in neutrophils, and inhibits bacterial growth. J. Biol. Chem. 275, 24490–24499 (2000)

    CAS  Article  Google Scholar 

  23. 23

    Liu, C., Xu, Z., Gupta, D. & Dziarski, R. Peptidoglycan recognition proteins: a novel family of four human innate immunity pattern recognition molecules. J. Biol. Chem. 276, 34686–34694 (2001)

    CAS  Article  Google Scholar 

  24. 24

    Stöven, S., Ando, I., Kadalayil, L., Engström, Y. & Hultmark, D. Activation of the Drosophila NF-κB factor Relish by rapid endoproteolytic cleavage. EMBO Rep. 1, 347–352 (2000)

    Article  Google Scholar 

  25. 25

    Ochiai, M. & Ashida, M. A pattern recognition protein for peptidoglycan. Cloning the cDNA and the gene of the silkworm, Bombyx mori. J. Biol. Chem. 274, 11854–11858 (1999)

    CAS  Article  Google Scholar 

  26. 26

    Sieling, P. A. & Modlin, R. L. Toll-like receptors: mammalian ‘taste receptors’ for a smorgasbord of microbial invaders. Curr. Opin. Microbiol. 5, 70–75 (2002)

    CAS  Article  Google Scholar 

  27. 27

    Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunol. 2, 675–680 (2001)

    CAS  Article  Google Scholar 

  28. 28

    Kimbrell, D. A. & Beutler, B. The evolution and genetics of innate immunity. Nature Rev. Genet. 2, 256–267 (2001)

    CAS  Article  Google Scholar 

  29. 29

    Jung, A., Criqui, M.-C., Rutschmann, S., Hoffmann, J.-A. & Ferrandon, D. A microfluorometer assay to measure the expression of β-galactosidase and GFP reporter genes in single Drosophila flies. Biotechniques 30, 594–601 (2001)

    CAS  Article  Google Scholar 

  30. 30

    Lemaitre, B., Reichhart, J. M. & Hoffmann, J. A. Drosophila host defense: differential display of antimicrobial peptide genes after infection by various classes of microorganisms. Proc. Natl Acad. Sci. USA 94, 14614–14619 (1997)

    ADS  CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank our colleagues in the laboratory for critical comments on the manuscript; L. Troxler and C. Hetru for computer analysis; and M. E. Moritz and M. Schneider for providing bacterial and fungal cultures. This work was supported by CNRS, the Ministère de l'Education Nationale de la Recherche et de la Technologie and the Foundation pour la Recherche Médicale (Implantation jeunes équipes to J.R and D.F.). Financial support from the National Institutes of Health is acknowledged.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Dominique Ferrandon or Julien Royet.

Ethics declarations

Competing interests

M.B. and G.D. are employees and shareholders in Exelixis Inc. The UPR 9022 du Centre National

de la Recherche Scientifique (CNRS) is partially funded by Exelixis Inc.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gottar, M., Gobert, V., Michel, T. et al. The Drosophila immune response against Gram-negative bacteria is mediated by a peptidoglycan recognition protein. Nature 416, 640–644 (2002). https://doi.org/10.1038/nature734

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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