Recognizing the intruder

Abstract

In recent years, Drosophila has emerged as a powerful genetic model for studying innate immunity. Although it has no adaptive immune system, it is very resistant to infection, as are all insects. Upon immune challenge, Drosophila synthesizes a battery of powerful antimicrobial peptides in the fat body – the equivalent of the mammalian liver. This defence mechanism, called the humoral response, is activated through two signalling pathways: the Toll pathway and the Imd pathway. The Toll pathway activates responses against fungi and Gram-positive bacteria, and it requires the Toll receptor protein and the NF-κB family transcription factor Dif. The Imd pathway is responsible for defences against Gram-negative bacteria, and it recruits the death-domain-containing protein Imd and the NF-κB family protein Relish.Many of the intracellular components of these two pathways have been identified, but little was known about how the initial recognition of microbial invasion occurred. Three new studies shed light on this process [1.xRequirement for a peptidoglycan recognition protein (PGRP) in relish activation and antibacterial immune responses in Drosophila. Choe, K.-W et al. Science. 2002; 296: 359–362Crossref | PubMed | Scopus (386)See all References, 2.xThe Drosophila immune response against Gram-negative infection is mediated by a putative membrane peptidoglycan recognition protein. Gottar, M et al. Nature. 2002; 416: 640–644Crossref | PubMed | Scopus (404)See all References, 3.xFunctional genomic analysis of phagocytosis and identification of a Drosophila receptor for E. coli. Ramet, M et al. Nature. 2002; 416: 644–648Crossref | PubMed | Scopus (491)See all References]. Two of the groups took a genetic approach to identify genes required for antibacterial response, one using a chemical mutagenesis screen, and the other, a P-element insertion library screen. The third group devised a dsRNA interference (RNAi)-based screen in cultured Drosophila macrophage-like cells looking for genes that influence bacterial phagocytosis. Eventually, the gene encoding the peptidoglycan recognition protein-LC (PGRP-LC) was isolated.This gene is predicted to encode a transmembrane protein with an extracellular peptidoglycan-binding domain. Peptidoglycan is implicated in the induction of innate immune defences in insects and mammals. In PGRP-LC mutants, activation of immune responses following infection by Gram-negative bacteria is severely impaired, and flies die soon after they are infected. Conversely, overexpression of PGRP-LC induces activation of the antibacterial peptide diptericin, which is used as a transcriptional read-out of the Imd pathway. Furthermore, cells depleted of PGRP-LC RNA are less able to phagocytose after infection with Escherichia coli and are not responsive to lipopolysaccharide.To clarify whether PGRP-LC was the sole element controlling activation by Gram-negative bacteria, Gottar et al. [2xThe Drosophila immune response against Gram-negative infection is mediated by a putative membrane peptidoglycan recognition protein. Gottar, M et al. Nature. 2002; 416: 640–644Crossref | PubMed | Scopus (404)See all References][2] generated a deletion of the gene's open reading frame. Both diptericin expression and survival after bacterial infection where less drastically influenced than in loss-of-function mutants for intracellular components of the Imd pathway. This indicates that there are other pattern recognition receptors that sense infection by Gram-negative bacteria. To this end, Ramet et al. [3xFunctional genomic analysis of phagocytosis and identification of a Drosophila receptor for E. coli. Ramet, M et al. Nature. 2002; 416: 644–648Crossref | PubMed | Scopus (491)See all References][3] observed that, although RNAi treatments had eliminated PGRP-LC RNA, phagocytosis was only decreased partially. Lastly, Gottar et al. evoke the question of how PGRP-LC signals to the Imd pathway. The absence of a transmembrane signalling domain would suggest PGRP-LC is a possible co-receptor of the putative Imd pathway receptor complex.It seems that the general picture emerging from these studies is that, as opposed to mammals, where infection is sensed by Toll-like receptors that bind directly to microbial patterns, in Drosophila, infection is sensed by circulating or transmembrane PGRPs, which transfer the ‘intruder alert’ signal to the intracellular humoral response pathways.