1. Institut de Biologie Moléculaire et Cellulaire, UPR 9022 du CNRS, 15 rue René Descartes, 67084 Strasbourg cedex, France

Correspondence to: Julien Royet Correspondence and requests for materials should be addressed to J.R. (e-mail: Email: J.Royet@ibmc.u-strasbg.fr).

Abstract

Microbial infection activates two distinct intracellular signalling cascades in the immune-responsive fat body of Drosophila^{1, 2}. Gram-positive bacteria and fungi predominantly induce the Toll signalling pathway, whereas Gram-negative bacteria activate the Imd pathway^{3, 4}. Loss-of-function mutants in either pathway reduce the resistance to corresponding infections^{4, 5}. Genetic screens have identified a range of genes involved in these intracellular signalling cascades^{6, 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.