The Toll and Imd pathways are the major regulators of the immune response in Drosophila
2002; Springer Nature; Volume: 21; Issue: 11 Linguagem: Inglês
10.1093/emboj/21.11.2568
ISSN1460-2075
AutoresEnnio De Gregorio, Paul T. Spellman, Phoebe Tzou, Gerald M. Rubin, Bruno Lemaître,
Tópico(s)Neurobiology and Insect Physiology Research
ResumoArticle3 June 2002free access The Toll and Imd pathways are the major regulators of the immune response in Drosophila Ennio De Gregorio Ennio De Gregorio Centre de Génétique Moléculaire, CNRS, F-91198 Gif-sur-Yvette, France Search for more papers by this author Paul T. Spellman Paul T. Spellman Department of Molecular and Cell Biology and Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, 94720-3200 USA Search for more papers by this author Phoebe Tzou Phoebe Tzou Centre de Génétique Moléculaire, CNRS, F-91198 Gif-sur-Yvette, France Search for more papers by this author Gerald M. Rubin Gerald M. Rubin Department of Molecular and Cell Biology and Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, 94720-3200 USA Search for more papers by this author Bruno Lemaitre Corresponding Author Bruno Lemaitre Centre de Génétique Moléculaire, CNRS, F-91198 Gif-sur-Yvette, France Search for more papers by this author Ennio De Gregorio Ennio De Gregorio Centre de Génétique Moléculaire, CNRS, F-91198 Gif-sur-Yvette, France Search for more papers by this author Paul T. Spellman Paul T. Spellman Department of Molecular and Cell Biology and Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, 94720-3200 USA Search for more papers by this author Phoebe Tzou Phoebe Tzou Centre de Génétique Moléculaire, CNRS, F-91198 Gif-sur-Yvette, France Search for more papers by this author Gerald M. Rubin Gerald M. Rubin Department of Molecular and Cell Biology and Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, 94720-3200 USA Search for more papers by this author Bruno Lemaitre Corresponding Author Bruno Lemaitre Centre de Génétique Moléculaire, CNRS, F-91198 Gif-sur-Yvette, France Search for more papers by this author Author Information Ennio De Gregorio1, Paul T. Spellman2, Phoebe Tzou1, Gerald M. Rubin2 and Bruno Lemaitre 1 1Centre de Génétique Moléculaire, CNRS, F-91198 Gif-sur-Yvette, France 2Department of Molecular and Cell Biology and Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, 94720-3200 USA *Corresponding author. E-mail: [email protected] The EMBO Journal (2002)21:2568-2579https://doi.org/10.1093/emboj/21.11.2568 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Microarray studies have shown recently that microbial infection leads to extensive changes in the Drosophila gene expression programme. However, little is known about the control of most of the fly immune-responsive genes, except for the antimicrobial peptide (AMP)-encoding genes, which are regulated by the Toll and Imd pathways. 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. We found that the Toll and Imd cascades control the majority of the genes regulated by microbial infection in addition to AMP genes and are involved in nearly all known Drosophila innate immune reactions. However, we identified some genes controlled by septic injury that are not affected in double mutant flies where both Toll and Imd pathways are defective, suggesting that other unidentified signalling cascades are activated by infection. Interestingly, we observed that some Drosophila immune-responsive genes are located in gene clusters, which often are transcriptionally co-regulated. Introduction Innate immunity plays a very important role in combating microbial infection in all animals. The innate immune response is activated by receptors that recognize surface determinants conserved among microbes but absent in the host, such as lipopolysaccharides, peptidoglycans and mannans (Medzhitov and Janeway, 1997). Upon recognition, these receptors activate multiple and complex signalling cascades that ultimately regulate the transcription of target genes encoding effector molecules. Importantly, different pathogens elicit specific transcription programmes that can now be investigated by using microarray technology (De Gregorio et al., 2001; Huang et al., 2001; Irving et al., 2001). Drosophila is devoid of an adaptive immune system and relies only on innate immune reactions for its defence. Genetic and molecular approaches have shown that Drosophila is a powerful model system to study innate immunity, which seems to be remarkably conserved from flies to mammals (Hoffmann and Reichhart, 2002; Tzou et al., 2002a). To combat microbial infection, Drosophila activates multiple cellular and humoral responses including, for example, proteolytic cascades that lead to blood coagulation and melanization, the production of several effector molecules such as antimicrobial peptides (AMPs) and the uptake of microorganisms by blood cells (Tzou et al., 2002a). AMPs are made in the fat body, a functional equivalent of mammalian liver, and secreted in the haemolymph, where they directly kill invading microorganisms (Hoffmann and Reichhart, 2002). Genetic analyses have shown that AMP genes are regulated by the Toll and Imd pathways (Hoffmann and Reichhart, 2002; Tzou et al., 2002a). The Toll pathway is activated mainly by Gram-positive bacteria and fungi and controls in large part the expression of AMPs active against fungi, while the Imd pathway responds mainly to Gram-negative bacteria infection and controls antibacterial peptide gene expression (Hoffmann and Reichhart, 2002; Tzou et al., 2002a). However, most of the AMP genes can be regulated by either pathway, depending on the type of infection, and the selective activation of Toll or Imd by different classes of pathogens leads to specific AMP gene expression programmes adapted to the aggressors. Thus, the control of AMP genes by the Toll and Imd pathways provides a good model to study how recognition of distinct microbes generates adequate responses to infection. The Imd and Toll pathways do not appear to share any intermediate components and mediate differential expression of AMP-encoding genes via distinct NF-κB-like transcription factors (Hoffmann and Reichhart, 2002; Tzou et al., 2002a). Upon infection, the Toll pathway is activated in the haemolymph by an uncharacterized serine protease cascade that involves the serpin Necrotic and leads to the processing of Spaetzle, the putative Toll ligand. Binding of Spaetzle to Toll activates an intracellular signalling cascade, involving the adaptor proteins dMyD88 and Tube, and the kinase Pelle, that leads to degradation of the Iκ-B-like protein Cactus and the nuclear translocation of the NF-κB-like transcription factors Dif and Dorsal (Hoffmann and Reichhart, 2002; Tzou et al., 2002a). An extracellular recognition factor, peptidoglycan recognition protein (PGRP)-SA, belonging to a large family of proteins that bind to peptidoglycan has been implicated in the activation of the Toll pathway in response to Gram-positive bacteria but not fungi (Michel et al., 2001). These data support the idea that the Toll pathway is activated by soluble recognition molecules that trigger distinct proteolytic cascades converging to Spaetzle. Recently, several studies have led to the genetic and molecular identification of seven components of the Imd pathway (Hoffmann and Reichhart, 2002; Tzou et al., 2002a). The ultimate target of the Imd pathway is Relish, a rel/NF-κB transactivator related to mammalian P105. Current models suggest that this protein needs to be processed in order to translocate to the nucleus. Its cleavage is dependent on both the caspase Dredd and the fly Iκ-B–kinase (IKK) complex. Epistatic experiments suggest that dTAK1, a MAPKKK, functions upstream of the IKK complex and downstream of Imd, a protein with a death domain similar to that of mammalian receptor-interacting protein (Hoffmann and Reichhart, 2002; Tzou et al., 2002a). Recently, three independent studies have shown that a putative transmembrane protein, PGRP-LC acts upstream of Imd and probably functions in sensing microbial infection (Choe et al., 2002; Gottar et al., 2002; Rämet et al., 2002b). The Drosophila Toll and Imd pathways share many features with the mammalian TLR/IL-1 and TNF-R signalling pathways that regulate NF-κB, pointing to an evolutionary link between the regulation of AMP gene expression in flies and the mammalian innate immune response (Hoffmann and Reichhart, 2002; Tzou et al., 2002a) We identified 400 Drosophila immune-regulated genes (DIRGs) through a microarray analysis of the transcription programmes induced by septic injury and by natural fungal infection (De Gregorio et al., 2001). Many of these genes were assigned to functions related to the immune response including, in addition to the AMP response, microbial recognition, phagocytosis, melanization, coagulation, reactive oxygen species (ROS) production, wound healing and iron sequestration. Although the regulation of AMP genes by Imd and Toll pathways has been studied extensively, little is known about the role of these two pathways in the control of other genes regulated by infection in Drosophila. In this study, we have characterized further the role of the Toll and Imd pathways in the Drosophila host defence. To study the contribution of each pathway in the resistance to infection, we first compared the susceptibility of flies carrying mutations affecting the Toll, Imd or both signalling cascades with several types of bacterial and fungal infection by a survival test. Secondly, we analysed, using northern blots, the expression of AMP genes after different types of infection in the same mutants. Finally, we monitored by microarray analysis the effect of mutations affecting the Toll and Imd cascades on the transcriptional reprogramming induced by septic injury. Our study demonstrates that the Toll and Imd pathways are the major regulators of the immune response in Drosophila adults. Results Contribution of the Toll and Imd pathways to resist microbial infection It has been shown that mutants of the Imd pathway are more susceptible than wild-type flies to Gram-negative bacterial infection, while mutants of the Toll pathway are more susceptible to fungal and Gram-positive bacterial infection (Lemaitre et al., 1996; Rutschmann et al., 2002). Three Drosophila lines carrying mutations affecting both the Toll and Imd pathways (imd;spz, imd;Tl and dif,kenny), have been reported to be sensitive to both bacterial and fungal infections (Lemaitre et al., 1996; Leulier et al., 2000; Rutschmann et al., 2000, 2002). However, these double mutant lines probably retain limited Toll or Imd activity because the imd allele is a hypomorph and dif mutants retain Dorsal activity (Georgel et al., 2001). We have generated double mutant Drosophila lines by recombining two strong alleles of the Toll pathway (spz: spzrm7 and Tl: Tl1-RXA/Tlr632) with a null allele of relish (rel: relE20). The comparison of the susceptibility to microbial infection of flies deficient for either the Toll (spz or Tl) or Imd (rel) pathway and flies mutated for both rel,spz or rel,Tl allows us to analyse in detail the contribution of each pathway to host defence. Wild-type OregonR (wt), single (rel, Tl and spz) and double mutant (rel,spz and rel,Tl) adult flies were injected with Gram-negative bacteria (Escherichia coli), Gram-positive bacteria (Micrococcus luteus and Enterococcus faecalis) and fungi (Aspergillus fumigatus) or were naturally infected with the spores of the entomopathogenic fungus Beauvaria bassiana (Figure 1). As previously observed, Tl and spz mutants are resistant to E.coli injection while rel flies are highly susceptible, dying within 3 days (Lemaitre et al., 1996; Hedengren et al., 1999; Leulier et al., 2000). Surprisingly, both double mutants (rel,spz and rel,Tl) are more susceptible than rel to E.coli infection, suggesting that the Toll pathway triggers a significant response against Gram-negative bacteria (Figure 1A). This is in agreement with a previous study showing that dif,kenny double mutants die earlier than kenny flies after infection by E.coli (Rutschmann et al., 2002). To study the contribution of Toll and Imd pathways to resist Gram-positive bacteria infection, we injected two bacterial strains: M.luteus, which does not kill flies deficient in the Toll or Imd pathway (Leulier et al., 2000); and E.faecalis, which kills spz flies very rapidly (Rutschmann et al., 2002). Interestingly, we noticed that double mutant lines are very sensitive to infection by M.luteus (Figure 1B) and that rel,spz double mutants are slightly more susceptible than spz flies to E.faecalis infection (Figure 1C). These data confirm that the Toll pathway is the most important pathway in fighting Gram-positive bacterial infection but indicate that the Imd pathway can also play a significant role. Finally, we observed that rel,spz and rel,Tl are almost equally as susceptible as single mutants in the Toll pathway (Tl or spz) to injection of A.fumigatus and to natural infection by B.bassiana, suggesting that the Imd pathway is not essential for the antifungal response (Figure 1D and E). Figure 1.Contribution of Toll and Imd pathways to the resistance to bacterial and fungal infections. Wild-type (wt), single (spz, Tl and rel) or double mutant (rel,spz and rel,Tl) adult flies were subjected to septic injury using E.coli (A), M.luteus (B), E.faecalis (C) and A.fumigatus (D) or to natural infection using B.bassiana (E). The graphs show the survival rate (%) at specific times after infection (h). All infection experiments were performed at 29°C, except for E.faecalis infection that was conducted at 25°C. Tl-deficient flies were not subjected to E.faecalis infection because they do not display a strong phenotype at 25°C (see Materials and methods). The presence of the ebony mutation in the rel mutant line may explain the slight susceptibility of rel flies after fungal infection (Leulier et al., 2000). Download figure Download PowerPoint Next, we analysed the effect of mutations affecting Imd and Toll pathways on the expression of AMP genes after injection of E.coli, M.luteus or A.fumigatus. Figure 2 shows a northern blot analysis of two antibacterial peptide genes (attacin and diptericin) and two antifungal peptide genes (drosomycin and metchnikowin). The double mutants rel,spz and rel,Tl failed to show induction of AMP genes. In fact, the only AMP transcript detectable in these flies is the antifungal drosomycin, which is present at a level similar to that in unchallenged flies. Diptericin is regulated by the Imd pathway, while metchnikowin, attacin and drosomycin are regulated by both pathways. Interestingly, the contribution of each pathway to the expression of each AMP gene depends on the type of infection. For example, in agreement with previous studies (Leulier et al., 2000), drosomycin expression is affected similarly by the rel and Toll pathway mutants after E.coli infection, but is regulated predominantly by the Toll pathway during M.luteus or A.fumigatus infections (Figure 2). Figure 2.Contribution of the Toll and Imd pathways to the induction of AMP genes. Total RNA was extracted from unchallenged wild-type flies (wt unch.) or 6 h after infection of wild-type (wt) single (spz, Tl and rel) or double mutant (rel,spz and rel,Tl) adult flies with E.coli (A), M.luteus (B) and A.fumigatus (C). Expression levels of attacin (att), diptericin (dipt) metchnikowin (metch) and drosomycin (drom) were measured by northern blotting. The signal of each AMP-encoding gene was quantified by PhosphorImager and normalized with the corresponding value of the rp49 gene. The graphs show the amount of each AMP transcript relative to the level measured in wild-type challenged flies that was set to 100. Northern blot analysis was carried out as in Leulier et al. (2000). Download figure Download PowerPoint The results obtained by northern blot analysis correlate with the data from survival experiments. The contribution of the two pathways to the control of the antibacterial peptides (Figure 2) is consistent with the augmented sensitivity to bacterial infection of double mutant flies versus single mutants (Figure 1A–C). The level of the antifungal peptide Drosomycin transcript after fungal infection is very similar in the double mutant flies (rel,spz and rel,Tl) compared with Tl and spz single mutants (Figure 2C), consistent with a similar resistance to A.fumigatus and B.bassiana displayed by these four lines (Figure 1C and D). Importantly, the Tl and spz alleles alone, or in combination with rel, display the same behaviour in all survival experiments performed (Figure 1) and have a similar pattern of AMP gene expression (Figure 2), suggesting that Spaetzle is the sole extracellular activator of the Toll pathway in response to microbial infection. However, we noticed that attacin and diptericin expression after A.fumigatus infection is reduced in Tl but not in spz flies (Figure 2C). We extended the analysis of A.fumigatus infection to pelle, tube and dif mutants (data not shown), which display the same AMP expression profile as spz, suggesting that the effect observed in Tl flies is due to the genetic background of the strain used. The complete survival and northern analysis presented here was extended to a strong allele of pelle alone or in combination with rel, which gave similar results to spz and Tl alleles (data not shown). The Toll and Imd pathways control the majority of Drosophila immune-regulated genes To identify which of the 400 previously identified DIRGs are controlled by the Imd and/or Toll pathways, mRNA samples from spz, rel and rel,spz adult males, collected after septic injury with a mixture of E.coli and M.luteus, were hybridized to Affymetrix DrosGenome1 GeneChips capable of measuring mRNA levels for nearly every gene in the Drosophila genome. The gene expression profiles obtained for the mutants flies were compared with our previous analysis of wild-type flies. Since double mutants start to die within 1 day after bacterial infection (Figure 1A and B), we limited our analysis to the first 6 h of the immune response (time points: 0, 1.5, 3 and 6 h), ensuring that the changes in expression profiles are not an indirect consequence of the sickness of the flies. In addition to loss-of-function mutants, we also observed the genome-wide changes in gene expression of uninfected Tl10b/+ flies carrying a gain-of-function allele that constitutively activates the Toll pathway. Each time series was observed in duplicate, while the Tl10b allele was assayed three times. Complete results can be found at http://www.fruitfly.org/expression/immunity/. General statistics and hierarchical cluster analysis Out of the 400 DIRGs previously identified, the majority (283) display a significant change in the expression pattern in the first 6 h (for each gene P <0.0025) (Figure 3A). Using an automated approach, we determined for each gene whether the gene expression profile is significantly different in a mutant background compared with wild-type (see Materials and methods). We observed that half of the 162 up-regulated genes examined (86) are not induced in rel,spz double mutants, 32 are partially affected and only 44 are still fully induced in this background (Figure 3A, upper table). Similar data were obtained from the analysis of 121 down-regulated genes, the majority of which are dependent (46) or partially dependent (27) on Relish and Spaetzle for their regulation, while 48 genes show no significant difference in rel,spz compared with wild-type flies (Figure 3A, lower table). Within the group of DIRGs affected in rel,spz flies, we could distinguish four categories based on their differential response to spz and rel mutations (see Venn diagrams in Figure 3A). Genes affected in rel but not in spz flies are probably controlled by the Imd pathway. In contrast, genes affected in spz flies but not in rel are probably controlled by the Toll pathway. We also found genes that are affected in both single mutants, which are probably regulated by both Imd and Toll pathways, and genes that are affected only in double mutant flies, suggesting that the two pathways play redundant roles in their regulation (Figure 3A). The tables in Figure 3A also show that 34 induced and 12 repressed DIRGs are regulated in Tl10b flies in the absence of infection. Interestingly, 34 of them are significantly affected in the rel,spz background and 23 in spz flies. It does appear that the Imd pathway may be less important in repressing DIRGs, as very few repressed DIRGs are only dependent on Relish (Figure 3A). Figure 3.Genome-wide analysis of the immune response in flies deficient in the Imd and Toll pathways. (A) General statistics on the effect of single (rel, spz and Tl10b) and double mutations (rel,spz) and on the induced and repressed DIRGs. The graphs show the number of DIRGs affected in rel (Rel), spz (Spz), both rel and spz (intersection between Rel and Spz) or only in the double mutant rel,spz (Rel-Spz). These groups were established by an automated statistical approach allowing the identification of significant differences in the gene expression profile between wild-type and mutant backgrounds. A complete list of the genes assigned to each group can be found as supplementary data available at The EMBO Journal Online. (B) Hierarchical cluster analysis of the 400 DIRGs. The expression profiles in response to septic injury using a mixture of E.coli and M.luteus of wild-type (wt) and mutant flies (spz, rel and rel,spz) are compared with the expression profiles of wild-type in response to B.bassiana natural infection and of Tl10b unchallenged flies. Columns correspond to different time points (indicated below in hours) and rows to different genes. Red indicates increased mRNA levels, whereas green indicates decreased levels compared with wild-type uninfected flies. Clusters of induced (UP) or repressed (D) co-regulated genes are indicated on the right. Download figure Download PowerPoint To analyse the gene expression profile in more detail, we hierarchically clustered all 400 DIRGs including previous data obtained after B.bassiana infection (time points: 0, 12, 24 and 24 h) and the complete kinetics of wild-type flies after septic injury (time points: 0, 1.5, 3, 6, 12, 24 and 48 h) (Figure 3B). We observe that most of the genes induced after fungal infection display a late or sustained response after septic injury and are not induced in spz and rel,spz flies, while they are fully induced in rel mutants and are up-regulated in unchallenged Tl10b flies (Figure 3B, cluster UP6). These data strongly suggest that this group of genes is controlled by the Toll pathway. In addition to the UP6 cluster, Spaetzle can regulate acute phase genes (UP5). In contrast to Spaetzle, Relish controls predominantly early and sustained phase genes, which are not induced by fungal infection or in Tl10b flies (UP4). Up-regulated genes independent from Relish and Spaetzle (clusters UP1 and UP3) are generally weakly induced by fungal infection and not affected by Tl10b. The analysis of repressed DIRGs shows that Spaetzle can regulate both early (D5 and D9) and late/sustained (D1 and D3) phase genes, while Relish partially controls a small number of early phase genes (D8). A large group of late phase genes repressed after fungal infection are regulated by both Relish and Spaetzle (D10). Interestingly, a second group of genes strongly repressed after fungal infection (D2) are not affected by rel and spz mutations but affected in Tl10b flies. Our analysis shows that the Toll and Imd pathways regulate the majority of the immune-responsive genes. However, the presence of genes not affected, or only partially affected, in the rel,spz background suggests that other pathways regulate the Drosophila immune response. Consistent with the survival experiments (Figure 1), we found that most of the genes induced by fungal infection are regulated by the Toll pathway after septic injury, without contribution of the Imd pathway, and that the two pathways contribute to the control of many genes induced only by bacterial infection. Target genes of Toll and Imd pathways To address which immune reactions are controlled by Relish, Spaetzle, both Relish and Spaetzle or by a still unknown mechanism, we examined the effect of the rel and spz mutations on the expression of selected DIRGs (Table I). Unlike our previous automated analysis, we used a less stringent approach. In Table I, we considered each gene affected by a mutation when we detected at least a 2-fold change in one time point in the mutant line compared with the corresponding time point in wild-type flies. As previously shown by northern blot analysis (Lemaitre et al., 1996; Hedengren et al., 2000), we found that most AMP genes are regulated by both Relish and Spaetzle, with the exceptions of attacin D and diptericin A, which are controlled only by Relish. Most of our results correlate with previous analyses. However, in contrast to northern blot analysis, we failed to detect an effect of the single spz mutation on the induction of drosomycin, and of the rel mutation on attacin A activation, suggesting that the cRNA probes from these genes can saturate the oligonucleotide microarray. Table 1. Effect of mutations affecting the Toll and Imd pathways on the expression of selected DIRGs CG number Name Function wt rel spz rel,spz Tl10b B.b. 1. Induced DIRGs Genes regulated by Relish CG14704 PGRP-LB Peptidoglycan recognition ++S 0 ++ 0 0 0 CG9681 PGRP-SB1 Peptidoglycan recognition ++++S ++ ++++ ++ ++ 0 CG7496 PGRP-SD Peptidoglycan recognition ++++S ++ ++++ + + 0 CG4437 PRGP-like Peptidoglycan recognition +S 0 + 0 0 0 CG2056 Ser-protease +L 0 + 0 0 0 CG9733 proPO-AE Ser-protease/melanization ++A 0 ++ 0 − 0 CG9453 Sp4 Serpin +S 0 + 0 0 0 CG10118 Pale Melanization +S 0 + 0 0 + CG9441 Punch Melanization ++A 0 ++ 0 0 0 CG4665 Dhpr Melanization +A 0 + 0 0 0 CG7629 Attacin D Antimicrobial peptide +++++S 0 +++++ 0 0 0 CG12763 DiptericinA Antimicrobial peptide ++++S − − ++++ − ++ 0 CG15829 Unknown peptide (82 amino acids) ++A 0 ++ 0 0 0 CG14027 TotM Stress response ++++S ++ ++++ ++ 0 + CG6898 Zip3 Iron metabolism +S 0 + 0 0 0 CG5576 imd IMD pathway +A 0 + 0 0 0 Genes regulated by Relish and Spaetzle (A) CG4559 Idgf3 Chitin binding/wound healing +S + + 0 0 0 CG6639 Ser-protease +L + + 0 +++++ ++++ CG3505 proPO-AE Ser-protease/melanization ++S ++ ++ + ++ + CG6687 Serpin ++L +++ ++ + +++ ++ CG18525 Sp5 Serpin +S + + 0 0 0 CG18550 yellow f Melanization +L + + 0 +++ + CG6524 Cp19 Melanization +S + + 0 0 + CG10810 Drosomycin Antimicrobial peptide ++S ++ ++ + ++ ++ CG8175 Metchnikowin Antimicrobial peptide ++S ++ ++ + ++ ++ CG10146 Attacin A Antimicrobial peptide ++++S ++++ ++++ + +++ ++ CG18372 Attacin B1 Antimicrobial peptide +++S +++ +++ + +++ + CG12494 Unknown peptide (61 amino acids) +L + + 0 0 0 CG8846 Thor Translation initiation +A + + 0 0 0 CG6667 Dorsal Toll pathway component +L + + 0 0 0 CG2163 Pabp2 Poly(A) binding +S + + 0 0 + CG2275 d-Jun JNK pathway/wound healing +A + + 0 0 0 CG7850 Puc JNK pathway/wound healing +A + + 0 0 0 (B) CG11709 PGRP-SA Peptidoglycan recognition +++S + ++ + + 0 CG14745 PGRP-SC2 Peptidoglycan recognition +S − − − − − 0 CG4432 PGRP-LC Peptidoglycan recognition +S 0 0 0 0 0 CG7052 Tep2 Complement-like +++S + 0 0 + + CG10363 Tep4 Complement-like +S 0 0 0 0 + CG4823 Complement binding +S 0 0 0 0 + CG11842 Ser-protease +L 0 0 0 ++ + CG9645 Ser-protease +S 0 0 − 0 ++ CG5909 Ser-protease ++A 0 + 0 0 ++ CG15046 Ser-protease ++A + + 0 0 0 CG6361 Ser-protease +S 0 0 0 0 0 CG11331 Serpin ++A ++ + 0 0 + CG3604 Kunitz family ++A 0 + 0 0 0 CG10697 Ddc Melanization +++A + ++ + 0 0 CG5550 Fibrinogen-like Coagulation +++A ++ ++ + 0 0 CG12965 Unknown peptide (45 amino acids) ++++S ++ 0 − +++ ++ CG9080 Unknown peptide (121 amino acids) +++A 0 ++ − − 0 + CG10812 Drosomycin B Antimicrobial peptide +L 0 0 − 0 + CG1385 Defensin Antimicrobial peptide ++++S − +++ 0 + + CG1878 Cecropin B Antimicrobial peptide +++++A ++ +++ 0 0 0 CG1373 Cecropin C Antimicrobial peptide ++++++A ++ ++++ − 0 0 CG6429 Unknown peptide (124 amino acids) +++A ++ ++ + 0 0 CG4269 Unknown peptide (102 amino acids) ++S 0 0 − 0 0 CG17278 Unknown peptide (49 amino acids) +A 0 0 0 0 0 CG8157 Unknown peptide (113 amino acids) +S 0 0 0 0 0 CG3666 Transferrin Iron metabolism +++A ++ ++ + 0 0 CG3132 β-galactosidase Lysosomal enzyme ++S 0 + 0 0 0 CG7279 Lip1 Lipase +S 0 0 0 0 0 CG4267 Lipase ++S + + 0 + 0 (C) CG10816 Drosocin Antimicrobial peptide ++++A ++ ++++ + ++ + CG10794 Diptericin B Antimicrobial peptide +++S ++ +++ + ++ 0 CG1365 CecropinA1 Antimicrobial peptide +++S ++ +++ − 0 0 CG1367 CecropinA2 Antimicrobial peptide ++++S ++ ++++ 0 0 0 CG4740 Attacin C Antimicrobial peptide +++++S +++ +++++ ++ +++ + Genes regulated by Spaetzle CG13422 GNBP-like Recognition +++S +++ + 0 +++ ++ CG12780 GNBP-like Recognition +S + 0 0 0 − CG8215 Ser-protease +L + 0 0 ++++ ++ CG9631 Ser-protease +L + 0 0 + 0 CG18563 Ser-protease +L + 0 0 ++++ CG1102 proPO-AE Ser-protease/melanization +S + 0 0 ++ 0 CG3066 proPO-AE Ser-protease/melanization ++S ++ + + + 0 CG16705 proPO-AE Ser-protease/melanization +S + 0 0 ++ + CG7219 Serpin ++++A ++++ 0 0 + 0 CG16713 Kunitz family ++S ++ + + ++ + CG18106 IM2 Unknown ++S ++ 0 0 +++ ++ CG15065 IM2-like Unknown +A + 0 0 0 + CG18108 IM2-like Unknown +++S +++ 0 0 +++ ++ CG15066 Unknown peptide (134 amino acids) +++S +++ − −
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