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Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein


Microbial infection activates two distinct intracellular signalling cascades in the immune-responsive fat body of Drosophila1,2. Gram-positive bacteria and fungi predominantly induce the Toll signalling pathway, whereas Gram-negative bacteria activate the Imd pathway3,4. Loss-of-function mutants in either pathway reduce the resistance to corresponding infections4,5. Genetic screens have identified a range of genes involved in these intracellular signalling cascades6,7,8,9,10,11,12, but how they are activated by microbial infection is largely unknown. Activation of the transmembrane receptor Toll requires a proteolytically cleaved form of an extracellular cytokine-like polypeptide, Spätzle13, suggesting that Toll does not itself function as a bona fide recognition receptor of microbial patterns. This is in apparent contrast with the mammalian Toll-like receptors14 and raises the question of which host molecules actually recognize microbial patterns to activate Toll through Spätzle. Here we present a mutation that blocks Toll activation by Gram-positive bacteria and significantly decreases resistance to this type of infection. The mutation semmelweis (seml) inactivates the gene encoding a peptidoglycan recognition protein (PGRP-SA). Interestingly, seml does not affect Toll activation by fungal infection, indicating the existence of a distinct recognition system for fungi to activate the Toll pathway.

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Figure 1: Expression of antimicrobial peptides in different mutant backgrounds after infection by fungi, Gram-positive or Gram-negative bacteria.
Figure 2: seml mutant flies are highly susceptible to Gram-positive infection.
Figure 3: seml is genetically upstream of Toll and nec, and codes for a circulating protein.
Figure 4: seml is a mutant for the Drosophila PGRP-SA gene.


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We thank our colleagues for comments on the manuscript, M. E. Moritz and M. Schneider for providing bacterial and fungal cultures, and C. Chevalier for sequencing. This work was supported by CNRS, the Ministère de l’Education Nationale de la Recherche et de la Technologie, and the Fondation pour la Recherche Médicale (Implantation jeunes équipes to J.R.). Financial support from Entomed, Exelixis and the National Institutes of Health is acknowledged.

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Correspondence to Julien Royet.

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

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