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

Microbial infection activates two distinct intracellular signalling cascade s in the immune-responsive fat body of Drosophila(1,2). Gram-positive bacte ria and fungi predominantly induce the Toll signalling pathway, whereas Gra m-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 intracel lular signalling cascades(6-12), but how they are activated by microbial in fection is largely unknown. Activation of the transmembrane receptor Toll r equires a proteolytically cleaved form of an extracellular cytokine-like po lypeptide, Spatzle(13), suggesting that Toll does not itself function as a bona fide recognition receptor of microbial patterns. This is in apparent c ontrast with the mammalian Toll-like receptors(14) and raises the question of which host molecules actually recognize microbial patterns to activate T oll through Spatzle. Here we present a mutation that blocks Toll activation by Gram-positive bacteria and significantly decreases resistance to this t ype of infection. The mutation semmelweis (seml) inactivates the gene encod ing a peptidoglycan recognition protein (PGRP-SA). Interestingly, seml does not affect Toll activation by fungal infection, indicating the existence o f a distinct recognition system for fungi to activate the Toll pathway.