Disease relevance of imd

• 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 [1].
• Mutants deficient for the Toll and imd pathways exhibit a severely reduced survival to fungal and bacterial infections, respectively [2].
• PGRP-LC and -LE recognize diaminopimelic acid (DAP)-containing peptidoglycans, which are cell wall components of many gram-negative bacteria and some gram-positive bacteria, and activate the imd pathway to produce antibacterial peptides [3].
• Recent studies of Drosophila immune responses have defined the immune deficiency (IMD) signaling pathway that mediates defense against Gram-negative bacterial infection [4].
• Dysregulation of apoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (SMA) [5].

Psychiatry related information on imd

• Congenital disorder of glycosylation IIc (CDG IIc), also termed leukocyte adhesion deficiency II, is a recessive syndrome characterized by slowed growth, mental retardation, and severe immunodeficiency [6].

High impact information on imd

• In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway [7].
• By genetic epistasis, we demonstrate that PGRP-LC acts upstream of the imd gene [1].
• NO induction of Diptericin reporters in the fat body required immune deficiency (imd) and domino [8].
• In Drosophila, the IMD pathway is required for antimicrobial gene expression in response to gram-negative bacteria [9].
• Using a two-hybrid screen in yeast, we have isolated the death protein dFADD as a molecule that associates with IMD [10].

Biological context of imd

• The importance of these peptides in host defense is supported by the observation that flies deficient for the Toll or Immune deficiency (Imd) pathway, which affects AMP gene expression, are extremely susceptible to microbial infection [11].
• Infection of Drosophila by Gram-negative bacteria triggers a signal transduction pathway (the IMD pathway) culminating in the expression of genes encoding antimicrobial peptides [12].
• We determined the molecular structure of the Imd pathway transcriptional activator Relish (GmmRel), which shows high amino acid identity and structural similarity to its Drosophila homologue [13].
• Here, we investigated the role of one of the two major pathways regulating innate immunity in invertebrates, the immunodeficiency (Imd) pathway, for Glossina morsitans morsitans's natural defence against Trypanosoma brucei spp. infections [13].
• We report the molecular characterization of the immune deficiency (imd) gene, which controls antibacterial defense in Drosophila. imd encodes a protein with a death domain similar to that of mammalian RIP (receptor interacting protein), a protein that plays a role in both NF-kappaB activation and apoptosis [14].

Anatomical context of imd

• Consistent with this, PGRP-LE binds to the diaminopimelic acid-type peptidoglycan, a cell-wall component of the bacteria capable of activating the imd pathway, but not to the lysine-type peptidoglycan [15].
• In Drosophila, microbial infection activates an antimicrobial defense system involving the activation of proteolytic cascades in the hemolymph and intracellular signaling pathways, the immune deficiency (imd) and Toll pathways, in immune-responsive tissues [15].
• Drosophila has evolved a potent immune system that is somewhat adapted to the nature of infections through the selective activation of either one of two NF-kappa B-like signalling pathways, the Toll and IMD (Immune deficiency) pathways [16].
• Mice lacking the mel-18 gene show a posterior transformation of the axial skeleton, severe combined immunodeficiency, and a food-passing disturbance in the lower intestine due to hypertrophy of the smooth muscle layer [17].
• In the mouse, more than 16 loci are associated with mutant phenotypes that include defective pigmentation, aberrant targeting of lysosomal enzymes, prolonged bleeding, and immunodeficiency, the result of defective biogenesis of cytoplasmic organelles: melanosomes, lysosomes, and various storage granules [18].

Associations of imd with chemical compounds

• The diaminopimelic acid (DAP)-type peptidoglycan potently activates imd-dependent induction of antibacterial peptides [19].
• Arachidonic acid, however, did not activate the imd pathway when used as the sole agonist [20].
• The in vitro system is capable of measuring lipopolysaccharide (LPS)-dependent activation of the immune deficiency (imd) pathway, which is similar to the tumour necrosis factor signalling pathway in mammals [20].
• Screening revealed that well-known inhibitors of phospholipase A(2) (PLA(2)), dexamethasone (Dex) and p-bromophenacyl bromide (BPB) inhibit LPS-dependent activation of the imd pathway [20].
• Its lack determines severe combined immunodeficiency in mammals, possibly due to accumulation of extracellular adenosine, which induces apoptosis in lymphocytes (Franco et al., 1998) [21].

Other interactions of imd

• We have expressed AMP genes via the control of the UAS/GAL4 system in imd; spätzle double mutants that do not express any known endogenous AMP gene [11].
• In an effort to identify additional components that influence Rel-domain gene function we have conducted a search for immunodeficiency mutants in Drosophila [22].
• We show that imd functions upstream of the DmIKK signalosome and the caspase DREDD in the control of antibacterial peptide genes [14].
• We also report that, in contrast to the antibacterial peptides, the antifungal peptide drosomycin remains inducible in a homozygous imd mutant background [23].
• Here we present evidence that induction of metchnikowin gene expression can be mediated either by the TOLL pathway or by the imd gene product [24].

Analytical, diagnostic and therapeutic context of imd

• After treatment with lysostaphin, which digests the cross-bridging peptides, S. aureus PGN weakly stimulated the IMD pathway, similar to M. luteus PGN [25].

References