Disease relevance of Tl

• Here we present a mutation that blocks Toll activation by Gram-positive bacteria and significantly decreases resistance to this type of infection [1].
• Gram-positive bacteria and fungi predominantly induce the Toll signalling pathway, whereas Gram-negative bacteria activate the Imd pathway [1].
• Interestingly, four of these genes are also required for Toll activation by fungi, while one is specifically associated with signaling in response to gram-positive bacterial infections [2].
• The Toll pathway mediates most defenses against Gram-positive bacteria and fungi, whereas the Imd pathway is required to resist Gram-negative bacterial infection [3].
• Flies lacking the eater gene displayed normal responses in NF-kappaB-like Toll and IMD signaling pathways but showed impaired phagocytosis and decreased survival after bacterial infection [4].

Psychiatry related information on Tl

• The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms [5].
• In addition, similar to Drosophila, Toll receptors and related proteins in the LRR superfamily may also be involved in human development, as well as in noninfectious human disease [6].

High impact information on Tl

• In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway [5].
• The Drosophila Persephone protease activates the Toll pathway when proteolytically matured by the secreted fungal virulence factor PR1 [7].
• The Toll pathway is required for the host response against fungal and most Gram-positive bacterial infections [7].
• The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults [8].
• The cytokine-induced activation cascade of NF-kappaB in mammals and the activation of the morphogen dorsal in Drosophila embryos show striking structural and functional similarities (Toll/IL-1, Cactus/I-kappaB, and dorsal/NF-kappaB) [8].

Biological context of Tl

• 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 [9].
• This pathway links a cell surface receptor to an apical caspase in invertebrate cells and therefore suggests that the Toll-mediated pathway of caspase activation may be the evolutionary ancestor of the death receptor-mediated pathway for apoptosis induction in mammals [10].
• In Drosophila the prototypic Toll regulates both embryonic development and adult immune response [11].
• This purified transcript complements the Toll mutant phenotype when injected into Toll- embryos, which proves that it is the Toll transcript [12].
• Structural basis for signal transduction by the Toll/interleukin-1 receptor domains [13].

Anatomical context of Tl

• Drosophila sex-peptide stimulates female innate immune system after mating via the Toll and Imd pathways [14].
• Consistent with this, Wek localizes to the plasma membrane of embryos, independently of Toll signaling [15].
• Unexpectedly, wek is dispensable for innate immune response, thus revealing differences in the Toll-mediated activation of Dorsal in the embryo and Dif in the fat body of adult flies [15].
• In contrast, when Toll, a "negative" target recognition molecule normally expressed by a subset of muscles that surrounds muscles 6 and 7, is misexpressed on muscles 6 and 7, the RP3 growth cone fails to exhibit its normal close contact with these muscles [16].
• We show here that the mature form of Spätzle triggers a Toll-dependent immune response after injection into the hemolymph of flies [17].

Associations of Tl with chemical compounds

• Drosophila immunity: a large-scale in vivo RNAi screen identifies five serine proteases required for Toll activation [2].
• Furthermore, systematic mutational analysis revealed that a conserved cysteine-containing motif, different from the cysteines used for the intermolecular disulfide linkages, serves as a self-inhibitory module of Toll [11].
• We show that ethylmethane sulfonate-induced mutations in the persephone gene, which encodes a previously unknown serine protease, block induction of the Toll pathway by fungi and resistance to this type of infection [18].
• Two components are known to mediate the signal transduction between Toll and Dorsal-Cactus: Pelle, a serine/threonine protein kinase, and Tube, a protein with an unknown biochemical activity [19].
• Here we report that Gram-negative diaminopimelic acid-type peptidoglycan is the most potent inducer of the Imd pathway and that the Toll pathway is predominantly activated by Gram-positive lysine-type peptidoglycan [20].

Physical interactions of Tl

• In dorsal-ventral patterning, the most widely accepted model of the pathway places Spätzle at the end of a ventrally restricted protease cascade that results in the proteolytic processing of the precursor form of Spätzle to an active ligand which is thought to bind to the Toll receptor [21].
• Tube and Pelle then transduce the signal from activated Toll to a complex of Dorsal and Cactus [22].

Regulatory relationships of Tl

• Hence, Spn43Ac negatively regulates the Toll signaling pathway, and Toll does not function as a pattern recognition receptor in the Drosophila host defense [23].
• Our results demonstrate that GNBP1 and PGRP-SA can jointly activate the Toll pathway [24].
• It has been proposed that Toll does not function as a pattern recognition receptor per se but is activated through a cleaved form of the cytokine Spaetzle [18].
• Spn27A controls the Toll pathway during early development and is involved in defence reactions in adult flies [25].
• We show that WntD acts as a feedback inhibitor of the NF-kappaB homologue Dorsal during both embryonic patterning and the innate immune response to infection. wntD expression is under the control of Toll/Dorsal signalling, and increased levels of WntD block Dorsal nuclear accumulation, even in the absence of the IkappaB homologue Cactus [26].

Other interactions of Tl

• 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 [27].
• Interestingly, seml does not affect Toll activation by fungal infection, indicating the existence of a distinct recognition system for fungi to activate the Toll pathway [1].
• Expression of the gene encoding the antifungal peptide Drosomycin in Drosophila adults is controlled by the Toll signaling pathway [28].
• Drosophila MyD88 is an adapter in the Toll signaling pathway [10].
• We investigate the activities of the Pelle kinase and Twist basic helix-loop-helix (bHLH) transcription factor in transducing Toll signaling [29].

Analytical, diagnostic and therapeutic context of Tl

• Sequence analyses show that Spätzle, the Drosophila melanogaster Toll-receptor ligand, shows striking similarity to nerve growth factor and coagulogen [30].
• Here, we used oligonucleotide microarrays to monitor the effect of mutations affecting the Toll and Imd pathways on the expression programme induced by septic injury in Drosophila adults [31].
• We report the molecular cloning of a class of putative human receptors with a protein architecture that is similar to Drosophila Toll in both intra- and extracellular segments [32].
• Using confocal immunofluorescence microscopy we also show that activated Toll induces a localized recruitment of Tube and Pelle to the plasma membrane [22].
• Viral infection induced a set of genes distinct from those regulated by the Toll or Imd pathways and triggered a signal transducer and activator of transcription (STAT) DNA-binding activity [33].

References