A recessive mutation, immune deficiency (imd), defines two distinct control pathways in the Drosophila host defense.

Abstract

In this paper we report a recessive mutation, immune deficiency (imd), that impairs the inducibility of all genes encoding antibacterial peptides during the immune response of Drosophila. When challenged with bacteria, flies carrying this mutation show a lower survival rate than wild-type flies. We also report that, in contrast to the antibacterial peptides, the antifungal peptide drosomycin remains inducible in a homozygous imd mutant background. These results point to the existence of two different pathways leading to the expression of two types of target genes, encoding either the antibacterial peptides or the antifungal peptide drosomycin.The powerful innate defense of higher insects involves proteolytic cascades (coagulation and phenoloxidase cascades), phagocytosis and encapsulation of invading microorganisms, and the synthesis by the fat body of a battery of potent antimicrobial peptides (reviewed in refs. 1 and 2). In Drosophila, several genes encoding inducible antibacterial peptides [cecropins (3, 4); diptericin (5); defensin (6); drosocin (7); M. Charlet, personal communication] and one inducible antifungal peptide [drosomycin (8); L.M. and J.-M.R., unpublished results] have been cloned. Understanding the mechanism of the coordinate control of their expression after immune challenge (e.g., septic injury) is a major goal in the field. Significant similarities exist between the control of antimicrobial peptide gene expression in insects and that of acute phase response genes in mammals (reviewed in refs. 1 and 2). This is illustrated by the involvement of common cis-regulatory motifs in the promoters of most of the insect and mammalian immune genes [e.g., NF-KB and NF-IL6 response elements, interferon consensus regulatory sequences (9-11)]. Furthermore, members of the Rel/NF-KB family play a crucial role in the transactivation of mammalian acute phase response genes; similarly, Rel proteins have been recently implicated in the control of the immune genes in Drosophila (12, 13) as the genes encoding the two Rel proteins dorsal (dl) and Dif (dorsal-related immune factor) are up-regulated in the fat body upon immune challenge and both proteins are translocated in the nucleus (refs. 12 and 13; B.L. and E.N., unpublished results). The precise roles of these proteins in the immune response of Drosophila are not yet established (discussed in refs. 14 and 15).While analyzing the expression of antibacterial genes in a mutant of the phenoloxidase cascade, we have found, by serendipity, a recessive mutation, immune deficiency (imd), that impairs the inducibility of the antibacterial peptides described so far in Drosophila. When challenged with bacteria, flies carrying this mutation show a lower survival rate than wild-type flies. We also report that, in contrast to the antibacterial peptides, the antifungal peptide drosomycin remains inducible in a homozygous imd mutant background. These results point to the existence of two different pathways leading either to the expression of the genes encoding antibact...

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

“…To achieve the expression of a single type of VSG on the surface, only 1 out of 20 possible telomeric VSG expression sites (ESs) is expressed at a given time 2 . A set of ESassociated genes 4 , which confers selective advantages in particular hosts 4,5 , are transcribed polycistronically together with the VSG from a promoter located 40±60 kilobases (kb) upstream 6,7 . Hence, VSG expression site regulation is a genuine example of a monoallelic expression from a multi-allelic gene family in an early branched eukaryote 8 .…”

“…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 identi®ed a range of genes involved in these intracellular signalling cascades 6±12 , but how they are activated by microbial infection is largely unknown.…”

“…diptericin expression is controlled by the Imd pathway, whereas induction of drosomycin is dependent on the Toll pathway 4,5 . From 2,500 independent lines, we isolated a mutant line in which the ability to express drosomycin in response to infection by Grampositive bacteria (Micrococcus luteus, Streptococcus faecalis, Bacillus thuringiensis) was abolished or severely reduced (Fig.…”

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

“…Notably, host defense against Gramnegative bacterial infection in Drosophila is mediated by a distinct recognition and signaling pathway defined by the Imd gene. 10 The recently identified Imd gene product contains a death domain with closest sequence similarity to the mammalian tumor necrosis factor-a receptorinteracting protein (RIP). 11 Imd regulates the expression of all antibacterial peptides, particularly those that are most active against Gram-negative bacteria, and in response to certain stimuli may also participate in the apoptotic response.…”

Antimicrobial peptide defense in Drosophila

“…The serendipitous discovery of a recessive mutant, irnd (for immune deficiency) (76), is a first indication for the existence of a second regulatory pathway: in homozygous imd mutants, the expression of the antibacterial peptide genes upon immune challenge is dramatically affected, whereas the drosomycin gene remains inducible. These data are summarized in Fig.…”