Positive and negative regulation of the Drosophila immune response

Abstract

Insects mount a robust innate immune response against a wide array of microbial pathogens. The hallmark of the Drosophila humoral immune response is the rapid production of antimicrobial peptides in the fat body and their release into the circulation. Two recognition and signaling cascades regulate expression of these antimicrobial peptide genes. The Toll pathway is activated by fungal and many Gram-positive bacterial infections, whereas the immune deficiency (IMD) pathway responds to Gram-negative bacteria. Recent work has shown that the intensity and duration of the Drosophila immune response is tightly regulated. As in mammals, hyperactivated immune responses are detrimental, and the proper down-modulation of immunity is critical for protective immunity and health. In order to keep the immune response properly modulated, the Toll and IMD pathways are controlled at multiple levels by a series of negative regulators. In this review, we focus on recent advances identifying and characterizing the negative regulators of these pathways. [BMB reports 2008; 41(4): 267-277]Insects rely primarily on innate immune responses to fight pathogens and have developed multiple mechanisms to recognize and respond to infection. The insect and mammalian innate immune responses exhibit a great deal of evolutionary conservation. One of the best examples of this conservation was provided by the discovery of the Toll pathway as a key component of the Drosophila immune response and the subsequent identification of the mammalian Toll-like Receptors (TLRs). In addition, the insect immune response relies on evolutionarily conserved NF-κB signaling cascades for the control of immune-induced gene expression. The genetic, genomic, and molecular tools available for studying the immune response in the fruit fly Drosophila melanogaster make this a favorite model system (1-4). Drosophila use several distinct effector mechanisms for immune protection including clotting, melanization, encapsulation, cell-based phagocytosis, and the inducible production of a battery of antimicrobial peptides. This antimicrobial peptide response is critical for protection against many microbial pathogens. Two signaling pathways regulate the production of these antimicrobial peptides in Drosophila -the immune deficiency (IMD) and Toll pathways. Recent work has shown that the intensity and duration of immune response is tightly regulated in Drosophila. As in mammals, over-exuberant immune responses are detrimental, and the proper down modulation of immunity is critical for health. In this review, we focus on the negative regulation of the IMD and the Toll pathway.

Comparative genomics allows the discovery of cis -regulatory elements in mosquitoes

“…The temporal-, tissue-, and sex-specific expression of groups of these genes is hypothesized to be under some form of coordinate regulation (15). Furthermore, it is proposed that this coordinate regulation is achieved by the presence of common CREs in control DNA in analogy to what is observed for hormone-, heat shock-, or immune-modulated genes in insects (16)(17)(18). Our findings support the conclusion that the shared life history of hematophagy in mosquitoes is a selective force in the conservation of CREs.…”

Role for σ38 in Prolonged Survival of Escherichia coli in Drosophila melanogaster

“…We thus tested the possibility that the rpoS-deficient E. coli was more sensitive to host immunity than the parental strain. There are two distinct immune responses against invading Gram-negative bacteria in Drosophila, the Imd pathway-mediated production of antimicrobial peptides (a humoral response) and the phagocytic elimination of bacteria by hemocytes (a cellular response) (12)(13)(14)(15)(16)(17). We first confirmed the occurrence of a humoral response in flies infected with E. coli.…”

“…The mechanism and meaning of innate immune responses have been studied in detail using fruit fly Drosophila melanogaster, a genetically tractable model animal equipped with only this type of immunity. Previous studies have revealed that substances located at the surface of pathogens are recognized by soluble and cell-bound receptors present in the hemolymph and the surface of immune cells called hemocytes, respectively, resulting in the induction of antimicrobial peptide production in the fat body and a variety of cellular immune reactions (12)(13)(14)(15)(16)(17). This mechanism of immunity against invading pathogens is fundamentally conserved beyond species including humans (18,19).…”

Post-transcriptional Regulation of Genes Encoding Anti-microbial Peptides in Drosophila

“…The ARE-mediated mRNA destabilizing mechanism identified here is probably one among several mechanisms involved in the down-regulation of genes activated by the Imd and Toll pathways (40). The variety of these processes underlines the importance for the fly to temper the expression of genes activated in response to infectious agents and in particular AMPep genes.…”