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 body. 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) pathway. Loss-of-function mutations in either pathway reduce the resistance to corresponding infections. 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). PGRPs appear to be highly conserved from insects to mammals, and the Drosophila genome contains 13 members. 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.

Methods to study Drosophila immunity

“…2A) and many mutations are done in the y,w background which shows higher immunoreactivity than for example ore R or Can S . The best way to activate the Imd pathway is to over-express Imd, PGRP-LC, PGRP-LE or the truncated, transcriptionally active form of Relish (Rel68) [44][45][46][47].…”

The road to Toll

“…In contrast to the rapid identification of TLRs and their ligands, the Drosophila molecules involved in microbial recognition remained unknown until recently. At present, we know that some aspects of microbial recognition in flies are mediated by peptidoglycan-recognition proteins (PGRPs) and Gram-negative-bacteria-binding proteins (GNBPs) 43,[56][57][58][59][60] -two protein families identified, initially in other insects, by their capacity to bind microbial components [61][62][63][64] (FIG. 3).…”

Toll-like receptors and their role in experimental models of microbial infection

“…12 Another so-called PGRP (PGRP-LC) bearing a transmembrane domain was shown to mediate activation of the Drosophila Imd pathway in response to Gram-negative infection, indicating that members of the PGRP family represent critical microbial PRRs. 13 Both soluble and membrane-bound mammalian PGRPs have been described, 14 although their role in microbial host defense has not yet been defined. Based on structural homology, eight other Toll receptors have been identified in the Drosophila genome; all of these are expressed and presumably function during embryonic development, yet so far only the original member (Toll1) has been strongly implicated in host defense functions.…”