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The Journal of Immunology, 2002, 168: 1542-1546.
Copyright © 2002 by The American Association of Immunologists

Cutting Edge

Cutting Edge: The Toll Pathway Is Required for Resistance to Gram-Positive Bacterial Infections in Drosophila1

Sophie Rutschmann, Ahmet Kilinc and Dominique Ferrandon2

Institut de Biologie Moléculaire et Cellulaire, Unité Propre de Recherche 9022 du Centre National de la Recherche Scientifique, Strasbourg, France


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 References
 
In Drosophila, the response against various microorganisms involves different recognition and signaling pathways, as well as distinct antimicrobial effectors. On the one hand, the immune deficiency pathway regulates the expression of antimicrobial peptides that are active against Gram-negative bacteria. On the other hand, the Toll pathway is involved in the defense against filamentous fungi and controls the expression of antifungal peptide genes. The gene coding for the only known peptide with high activity against Gram-positive bacteria, Defensin, is regulated by both pathways. So far, survival experiments to Gram-positive bacteria have been performed with Micrococcus luteus and have failed to reveal the involvement of one or the other pathway in host defense against such infections. In this study, we report that the Toll pathway, but not that of immune deficiency, is required for resistance to other Gram-positive bacteria and that this response does not involve Defensin.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 References
 
The Drosophila host defense consists of both humoral and cellular reactions (1). The cellular arm of the response is mediated by hemolymphatic cells, plasmatocytes, that phagocytose microorganisms. A septic injury triggers several protease cascades, some of which induce melanization reactions at the site of injury. These reactions are thought to contribute to host defense by the production of reactive oxygen species that may participate in the killing of microorganisms (2, 3). However, an essential feature of the humoral response is the secretion by the fat body, a functional equivalent of the liver, of potent antimicrobial peptides. These peptides are active against a limited range of microorganisms (4). For instance, Drosomycin is active on filamentous fungi, whereas Diptericin was purified as an anti-Gram-negative peptide in the fly Phormia terranovae (5, 6). Drosophila Diptericin and Attacin are thought to be active on Gram-negative bacteria. In addition to its main anti-Gram-negative activity, Cecropin has been reported to be also active on fungi (7). Defensin is the peptide that displays the major anti-Gram-positive activity in Drosophila (P. Bulet, personal communication) (8). Mutants which affect the regulatory pathways that control the inducibility of the antimicrobial peptide genes have been characterized. Interestingly, such mutants were found to succumb rapidly to microbial infections. These findings suggested, but did not demonstrate, that antimicrobial peptides are major effectors of Drosophila innate immunity.

Genetic analysis has shown that the expression of antimicrobial peptide genes is controlled by at least two distinct pathways (1, 9). The Toll pathway regulates the transcription of Drosomycin, and partially that of Defensin (10, 11, 12). This regulatory pathway appears to be preferentially activated by Gram-positive bacteria and fungi (11, 13). Toll pathway mutant flies succumb rapidly to fungal infections but not to a Gram-negative bacterial challenge (10, 11). Conversely, flies mutated for genes of the immune deficiency (imd)3 pathway are susceptible to Gram-negative infections, but are as resistant as wild-type flies to natural infections with spores of the entomopathogenic fungus Beauveria bassiana. The imd pathway controls the expression of all known Drosophila antibacterial peptides, including Diptericin and Defensin (14, 15, 16, 17, 18, 19, 20, 21, 22). However, neither pathway appeared to be required for resistance against Micrococcus luteus, a microorganism that was classically used as a Gram-positive bacterial inducer (this work and Ref. 16). In this report, we show that mutants of the Toll pathway, but not of the imd pathway, succumb to other Gram-positive bacterial infections.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 References
 
Fly strains

Fly cultures were grown on standard medium at 25°C. yellow (y) white (w) DD1; cinnabar brown (cn bw) flies were used as wild-type control. They carry both pdipt-LacZ and pdrom-GFP transgenes on the X chromosome (DD1) (11). Dif1, key1, spzrm7, and Df(2L)J4b lines are described in Flybase (http://flybase.harvard.edu/).

Septic injuries and survival experiments

Septic injuries were performed at 20°C by pricking adult flies with a thin tungsten needle previously dipped into a concentrated culture of the following bacteria: Escherichia coli 1106, M. luteus (CIP A270), or a mixture of both, or Enterococcus faecalis. All bacterial strains are generous gifts from H. Monteil (University Louis Pasteur, Strasbourg, France), except for Bacillus megaterium and Bacillus thuringensis (CIP 53137) that were kindly donated by J. Millet and A. Klier (Institut Pasteur, Paris, France).

Survival experiments were performed in the same conditions for each genotype tested. Groups of 25 adult females, ages from 5 to 7 days, were challenged with E. coli or E. faecalis, grown at 29°C for E. coli infections and at 25°C for E. faecalis, and transferred to fresh vials every 2 days. The flies that died within 3 h following the injury were not considered in the analysis.

RNA preparation for Northern blot analysis

Northern blot analysis was conducted as previously described (14) except that total RNA was prepared from 15 flies using a TRIzol (Life Technologies, Rockville, MD) extraction protocol.

Phagocytosis tests

Indian ink (Pébéo, Gemenos, France) diluted 1/50 in PBS was injected using a Nanoject microinjector (Drummond Scientic, Broomall, PA) in wild-type or Dif1 third instar larvae hemocoel. The phagocytosis of indian ink by the sessile blood cells was monitored 2 h later. FITC-labeled Staphylococcus aureus were purchased from Molecular Probes (Eugene, OR) and prepared according to the manufacturer’s instructions. Briefly, 32.2 nl of FITC-labeled bacteria were injected in the abdomen on the ventral lateral side using a Nanoject (Drummond Scientific). If needed, 400 nl of a 0.4% trypan blue solution (Sigma-Aldrich, St. Louis, MO) was injected in the thorax 30–45 min after the injection of bacteria. To saturate the phagocytic system, 200 nl of Surfactant-free Red CML latex beads (0.28 µM diameter; Interfacial Dynamics, Eugene, OR) was injected in the abdomen 4–6 h before the experiment. Injected flies were observed using a Leica MZ FLIII dissecting microscope and photographs were taken using a digital charge-coupled device Spot RT color camera (Diagnostic Instruments, Sterling Heights, MI).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
References
 
The Drosophila systemic antimicrobial response is not necessary to resist M. luteus infections

In the course of a large genetic screen of the second chromosome, we have identified mutants in both pathways of the humoral response: the dorsal-related immunity factor (Dif) in the Toll pathway and kenny (key) in the imd pathway (11, 15). We and others have previously shown that DIF is the transcription factor that mediates the activation of the Toll pathway in adults (11, 12). key encodes the Drosophila homologue of the vertebrate I-{kappa}B kinase {gamma} (IKK{gamma}) gene. Its corresponding protein has been shown to form a complex with the Drosophila IKK{beta} kinase that phosphorylates the Rel transcription factor Relish (23). Relish is the transactivator of the imd pathway (18). Dif and key mutants present the usual phenotypes of strong loss of function mutations in their respective pathways. In addition, both of them resist a challenge with M. luteus (data not shown). To determine whether the response to Gram-positive bacteria is dependent on both pathways as reported by Leulier et al. (16) in a previous study, we constructed a Dif-key double mutant strain. Thus, we had generated mutant lines that inactivate one, the other, or both pathways in the same genetic background: this allowed us to compare rigorously their phenotypes. We have analyzed the expression of the antimicrobial peptide genes in response to a challenge with a mixture of E. coli (Gram negative) and M. luteus in these mutant flies. As expected, the immune inducibility of all tested antimicrobial genes is drastically reduced in the Dif-key double mutants (Fig. 1Go). Remarkably, we found that Dif-key double mutants are as resistant as our wild-type reference strain to M. luteus infection (data not shown). Since the systemic antimicrobial response is virtually abolished in this background, this finding suggests that the cellular response may be sufficient to dispose of this microorganism (17).



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  		FIGURE 1. The immune inducibility of antimicrobial genes is drastically reduced in Dif-key double mutants. Batches of 15 females of each indicated genotype have been injured with a mixture of Gram-negative (E. coli 1106) and Gram-positive (M. luteus) bacteria. Northern blot analysis was performed as described in Materials and Methods. The same Northern blot has been hybridized sequentially to Diptericin, Cecropin, Attacin, Defensin, Metchnikowin, Drosomycin, and Ribosomal Protein 49 (RP 49) probes. RP 49 was used as loading control. The genotypes and the time points (in hours) are indicated at the bottom (0, unchallenged). WT = wild-type reference strain with a second chromosome marked by cinnabar (cn) and brown (bw) in which the Dif and key mutants were generated.

 
Sensitivity of Toll pathway mutant flies to other Gram-positive bacterial strains

The M. luteus strain we use was initially chosen for its low pathogenicity to humans. We therefore tested other Gram-positive strains: Bacillus megaterium, Staphylococcus hemolyticus, Pediococcus acidolactici, E. faecalis, Staphylococcus saprophyticus, and B. thuringiensis. The first two strains behaved as M. luteus. In contrast, flies infected with B. thuringiensis succumbed too rapidly to note a significant difference between the different mutant fly strains. However, for P. acidolactici, E. faecalis, and S. saprophyticus infections, we observed that Dif mutant flies died more rapidly than wild-type control and key flies (Fig. 2Go and data not shown). Interestingly, Dif-key mutant flies succumb at the same rate as Dif flies, indicating further that the key gene is not required for resistance to such Gram-positive infections.



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  		FIGURE 2. Toll pathway mutants are sensitive to Gram-positive (E. faecalis) but not to Gram-negative (E. coli) infections. A, Five- to 7-day-old flies were infected using a thin tungsten needle previously dipped in a concentrated E. faecalis solution. Batches of 25 flies were kept in vials at 25°C, counted every day (D), and vials were changed every 2 days. Survival rates are expressed in percentage of flies still alive 3 h after injury. These experiments have been repeated at least three times. Similar results have been obtained with S. saprophyticus and P. acidolactici Gram-positive bacteria. The genotypes are indicated on the right. J4, deficiency which uncovers Dif and dorsal (12 ). The Dif1/J4 flies show that the susceptibility to E. faecalis is not due to a second site mutation on the Dif chromosome. B, An experiment similar to that described in A was conducted at 29°C with the Gram-negative bacteria E. coli.

 
To ascertain whether the whole Toll pathway is required for the resistance to these Gram-positive bacteria, we tested mutants of the most upstream known component of this pathway: spätzle (spz) (24). This gene codes for the putative ligand of the Toll receptor. Indeed, spz mutant flies are also sensitive to E. faecalis infections (Fig. 2Go). We conclude from these experiments that the Toll pathway is necessary for resistance against Gram-positive bacterial infections, whereas the imd pathway appears to be dedicated to the response against Gram-negative bacteria.

Effectors of the Gram-positive antibacterial response?

It has been reported that Gram-positive bacteria are stronger inducers of the Toll pathway than Gram-negative bacteria (11, 13). Thus, our finding that this pathway is also involved in the host defense against Gram-positive infections sheds a new light on this observation.

To correlate the E. faecalis sensitivity phenotype observed in Toll pathway mutants to the pattern of antimicrobial peptide genes expression, we performed Northern blot analysis on flies challenged with this microorganism (Fig. 3Go). As expected, we found that Drosomycin is more strongly induced by E. faecalis than by E. coli and that its expression is dramatically reduced in spz and Dif flies, but not in key mutants. In agreement with previous experiments performed using M. luteus as an elicitor, the mild Diptericin inducibility obtained with an E. faecalis challenge is abolished in key, but not in spz and Dif flies. Strikingly, the expression of the main anti-Gram-positive peptide gene, Defensin, reaches similar low levels in all tested mutant backgrounds after immunization with E. faecalis. We conclude that Defensin is not necessary for resistance against this Gram-positive bacterium since key mutants do not express Defensin at high levels, yet are resistant to this microorganism. This observation suggests that other presently unknown mechanisms could play a role in the defense against this infection. Indeed, several peptides with unidentified function were detected in the hemolymph of infected flies, and most of these are controlled by the Toll pathway (25). None of these Toll-controlled peptides appear to have an obvious antimicrobial activity (P. Bulet, unpublished observations). In addition, recent experiments performed with DNA chip technology indicate that up to 146 genes of 8800 testable genes are specifically up-regulated at least by a factor 2 by a Gram-positive bacteria challenge (26). These genes may include unknown effectors of the Drosophila Gram-positive response, some of which may be controlled by the Toll pathway. Alternatively, we cannot rigorously exclude a role for the cellular response in this process. However, we found that Dif mutant larval hemocytes are able to phagocytose indian ink particles as well as wild-type controls (data not shown). This observation suggests that the basic mechanisms of phagocytosis are not affected in Toll pathway mutants. Furthermore, we have assayed the phagocytosis of FITC-labeled Gram-positive bacteria (S. aureus) by wild-type and Dif mutants using a technique developed by Elrod-Erickson et al. (17) for Gram-negative bacteria. As previously reported, we found that injected FITC-labeled bacteria are rapidly phagocytosed, mostly by sessile hemocytes (Fig. 4GoA). Indeed, the fluorescence associated with noningested bacteria is quenched by injected trypan blue, whereas phagocytosed bacteria are protected from the action of the dye since viable cells do not take it in (Fig. 4GoB). To demonstrate the specificity of the signal, we repeated the experiment in flies injected with latex beads a few hours beforehand to saturate and thus inhibit the phagocytic system. We did detect individual fluorescent bacteria in the hemolymph, but could not detect much fluorescence associated with sessile hemocytes (most easily observed on the dorsal vessel, Fig. 4GoC). As expected, this fluorescence was quenched by trypan blue (Fig. 4GoD), an indication that the bacteria could no longer be phagocytosed (17). Next, we performed the whole set of experiments in a Dif mutant background and found similar results (Fig. 4Go, E–H). These data suggest that phagocytosis of Gram-positive bacteria is not altered in Toll pathway mutants, at least in qualitative terms.



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  		FIGURE 3. Induction of antimicrobial peptides genes by E. faecalis suggests that Defensin is not needed for Drosophila host defense against this pathogen. Batches of 15 females of each genotype have been injured with E. coli or E. faecalis. Northern blot analysis has been performed as described in Materials and Methods. The same Northern blot has been hybridized sequentially to Drosomycin, Defensin, Diptericin, and RP 49 probes. The genotypes are indicated on the top, whereas the inducers and the time of incubation (in hours) are indicated at the bottom. U. C., unchallenged. The wild-type control in this experiment is the cnbw/J4 transheterozygous strain.

 


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  		FIGURE 4. Phagocytosis of FITC-labeled S. aureus is not affected in Dif mutant flies. A–D, Wild-type flies at 64-fold magnification. E–H, Dif1 mutant flies at 64-fold magnification. A and E, Flies injected with FITC-labeled S. aureus. The fluorescence is seen all over the fly, but is concentrated in multiple foci that may correspond to islands of sessile hemocytes. These are easy to visualize on the dorsal vessel. B and F, Same as A and E except that trypan blue was injected 30 min after the injection of labeled bacteria. Most of the background fluorescence has disappeared except in the sessile hemocytes. Exposure time has been doubled as compared, respectively, to A and E. C and G, Same as A and E except that flies have been previously injected with latex beads to saturate the phagocytic apparatus of hemocytes. The fluorescence is no longer concentrated in foci and single bacteria can be seen flowing in the hemolymph, especially in the transparent legs and wings. D and H, Same as C and G except that trypan blue has been injected 30 min after the injection of labeled bacteria. The remaining fluorescence is much weaker.

 
Conclusion

In summary, we have shown that the Toll pathway is required for resistance to some Gram-positive bacterial infections and that the imd pathway is not. The former had been previously shown to play a fundamental role in the defense against filamentous fungi. In addition to its immunological functions, this pathway also controls the establishment of dorso-ventral polarity in the Drosophila embryo (24, 27). In vertebrates, the Toll pathway has been implicated in the activation of NF-{kappa}B following the detection of microbial components by several distinct members of the Toll-like family of receptors (TLR) (28, 29, 30). For instance, TLR4 mediates the activation of NF-{kappa}B by LPS, the main component of the outer membrane of Gram-negative bacteria, whereas TLR2 plays a similar role in response to peptidoglycan, the major constituent of the Gram-positive cell wall (31, 32). In contrast, the same Toll receptor is required for the response to both fungal and Gram-positive bacterial elicitors in Drosophila. This suggests that in this system, the recognition step that discriminates between these distinct pathogens takes place further upstream of the Toll receptor. Indeed, the peptidoglycan recognition protein SA has recently been shown to play a major role in the activation of the Toll pathway (33). Although the mechanisms that allow the identification of Gram-positive bacteria have long been unknown but are beginning to be deciphered, we paradoxically do not yet understand well the effector arm of the Drosophila immune response. Indeed, the systemic antimicrobial response (through Defensin) and the cellular response do not appear to play a major role in the defense against some virulent Gram-positive bacterial strains. A major challenge of the coming years will be to understand how the Toll pathway manages its multiple roles in Drosophila host defense.


   Acknowledgments
 
We thank Jules Hoffmann for his continuous interest in our work; J. Hoffmann, Marie Gottar, and Vanessa Gobert for critical reading of this manuscript; and René Lanot for help with the phagocytosis test. Martine Schneider and Raymonde Syllas are gratefully acknowledged for their technical help.


   Footnotes
 
1 This work was supported by the Centre National de la Recherche Scientifique, National Institutes of Health Grant 1PO1 AI44220-02, the French Ministère de l’Education Nationale, de la Recherche et de la Technologie (Programme de Recherche Fondamentale en Microbiologie et Maladies Infectieuses et Parasitaires). Back

2 Address correspondence and reprint requests to Dr. Dominique Ferrandon, Institut de Biologie Moléculaire et Cellulaire, Unité Propre de Recherche 9022 du Centre National de la Recherche Scientifique, 15, rue R. Descartes, F67084 Strasbourg, Cedex, France. E-mail address: D.Ferrandon{at}ibmc.u-strasbg.fr Back

3 Abbreviations used in this paper: imd, immune deficiency; Dif, dorsal-related immunity factor; IKK, I{kappa}B kinase; TLR, Toll-like receptor, key, kenny; spz, spätzle. Back

Received for publication October 29, 2001. Accepted for publication December 14, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 References
 

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