TEAM

Host pathogen interaction in the Drosophila model

Group leader : J. Royet

Our lab is studying the interactions that are taking place between bacteria and the gut epithelium using Drosophila as a model system.

FOR BEGINNERS

Anterior domain of a Diptericin-cherry larval midgut infected with GFP-labbeled bacteria and stained with DAPI.

Recent technological advances have enabled us to grasp the incredible diversity of bacterial species that inhabit our digestive tract. 1014 bacteria belonging to hundreds of different species are housed in our intestine. This microbial population, called microbiota, is nowadays considered as an extra internal organ. It appears that, in addition to it’s essential physiological functions for the host (helping digestion, facilitating assimilation of nutrients) microbiota also influences our capacity to fight infection, to control our weight and can even modulate our nervous system functioning. Although in constant contact with these bacteria, the gut cells do not trigger an immune reaction. If defective, this phenomenon known as immune tolerance, can lead to a chronic inflammation of the digestive tract, a common condition in the human population. In part because of its amenability to genetic manipulation, the Drosophila or fruit fly, has recently emerged as a model system for the study of the innate immune response (Nobel Prize in Medicine, 2011). Recent studies show that Drosophila, like human, has a microbiota providing essential functions for the host and being tolerated by the intestinal epithelium. Taking advantage of the power of Drosophila genetics, our lab ambitions to dissect the molecular dialogue established between bacteria of the digestive tract and the host organs. In addition, we try to understand the mechanisms by which the intestinal epithelium tolerates the presence of bacteria that in other tissues triggers a strong immune response. Conservation during evolution, of multiple immunity mechanisms, raises hope that our work will have an impact on our understanding of host-bacteria interactions in higher eukaryotes, including humans.

A rare case of smiling mitochondria !

The lab is also interested in the mechanisms which control the morphology of mitochondria. Those organelles, that are the main power supply of the cell, form highly dynamic networks which morphology is frequently remodeled by fission and fusion.  In Human, genetic alterations that affect mitochondrial remodeling cause neuromuscular disease (CMT2A) and optic atrophy (ADOA). Our laboratory has identified a novel protein which controls mitochondrial morphogenesis in both drosophila and human cells. Taking advantage of the genetic tools and the in vivo imaging techniques available in drosophila, we are investigating the molecular basis of mitochondrial morphogenesis and its physiological role.

FOR SPECIALISTS

Our laboratory uses Drosophila to dissect the molecular mechanisms that govern interactions between bacteria and their host. Thanks to the existence of a high evolutionary conservation of most immune mechanisms (phagocytosis, antimicrobial peptides production, immune signaling pathways …), we can take advantage of the relative simplicity of an invertebrate model to discover process that may be in part conserved in humans.

  • Some species of microorganisms are pathogenic and can induce significant biological malfunction in the infected host and, in some cases, cause death. Maintaining harmony in the living world therefore requires a balance between organisms seeking to protect themselves from pathogens and microbes that try to circumvent host defenses. Face to the same major groups of microorganisms (bacteria, viruses, fungi, yeasts …), the vegetal and animal species have developed their own defense systems during evolution. If the molecular mechanisms implemented differ, the goals to be achieved remain the same. The contaminated organism must firstly identify the pathogen and then neutralize it. Invertebrates do not have, like vertebrates, an adaptive immune system leading amongst others to the production of antibodies. They fight infectious agents only with their innate immune system, which produces notably antimicrobial peptides. The synthesis of these molecules is subject to a preliminary step of microorganism identification. Relying on the power of Drosophila genetics, we have identified the main receptors used by Drosophila to detect the presence of bacteria.

    Proventriculus of a PGRP-LE GFP, Dipt-Cherry transgenic larvae stained with DAPI.

PGRP proteins are essential bacterial receptors

The work of the team has shown that proteins called PeptidoGlycan Recognition Proteins (PGRP) play a vital role in the detection of bacteria. As their name suggests, these proteins bind peptidoglycan (PGN), an essential component of the bacterial cell wall. This interaction PGRP-PGN triggers signaling pathways that are very close to those of the vertebrate immune pathways such as TNF-a, interleukin-1 or Toll Like Receptors. Our work on PGRPs have enabled us to show that

  • Drosophila detects bacteria through their PGN and not through their Lipopolyssacharides
  • The drosophila immune system can distinguish between Gram-negative and Gram-positive bacteria and trigger appropriate responses
  • A non-controlled immune response in Drosophila is deleterious as in humans, were it leads to septic shock. Some PGRP proteins not only recognize PGN but also cleave it, and are actively involved in this immune modulation.

Future directions : study of the microbiota/host interaction

Dipt-cherry larvae orally infected with Ecc-GFP bacteria.

Our laboratory is now interested in the complex interactions between bacteria of the digestive tract and Drosophila. The recent advent of high-throughput sequencing showed that our intestine contains thousands of bacteria belonging to hundreds of species. It is considered that the genome of these bacteria gathers 100 times more genes than our cells. Recent studies from several laboratories have shown that drosophilia’s microbiota is much simpler than the man’s one with about 10 to 20 bacterial species. In addition, our laboratory and others have demonstrated that these intestinal bacteria can strongly influence some aspects of their host as their growth or their mating preference. Our goal in the coming years is to combine the power of imaging, the simplicity of intestinal microbiota in Drosophila and the immense diversity of genetic tools for

  • Understanding how bacteria are detected but meanwhile tolerated by the cells of the intestinal epithelium
  • Assess the importance of the bacteria presence on the gut epithelial homeostasis and the consequences of a tolerance break on this homeostasis
  • Apprehend the consequences of commensal bacteria presence on host physiology

Main publications

PUBLICATION

Oligopeptide Transporters of the SLC15 Family Are Dispensable for Peptidoglycan Sensing and Transport in Drosophila.

Capo F, Chaduli D, Viallat-Lieutaud A, Charroux B, Royet J.
J Innate Immun. 2017;9(5):483-492. doi: 10.1159/000475771. PMID: 28715804

PUBLICATION

Peptidoglycan sensing by octopaminergic neurons modulates Drosophila oviposition.

Kurz CL, Charroux B, Chaduli D, Viallat-Lieutaud A, Royet J.
Elife. 2017 Mar 7;6. PMID: 28264763

PUBLICATION

Inhibition of a NF-κB/Diap1 Pathway by PGRP-LF Is Required for Proper Apoptosis during Drosophila Development

Tavignot R, Chaduli D, Djitte F, Charroux B, Royet J.
PLoS Genet. 2017 Jan 13;13(1):e1006569. PMID: 28085885
Other publications

PUBLICATION

Bacteria sensing mechanisms in Drosophila gut: Local and systemic consequences.

Capo F, Charroux B, Royet J.
Dev Comp Immunol. 2016 Jan 8. PMID: 26778296

PUBLICATION

Tissue-Specific Regulation of Drosophila NF-x03BA;B Pathway Activation by Peptidoglycan Recognition Protein SC.

Costechareyre D, Capo F, Fabre A, Chaduli D, Kellenberger C, Roussel A, Charroux B, Royet J.
J Innate Immun. 2016;8(1):67-80. PMID: 26513145

PUBLICATION

Drosophila Microbiota Modulates Host Metabolic Gene Expression via IMD/NF-κB Signaling.

Combe BE, Defaye A, Bozonnet N, Puthier D, Royet J, Leulier F.
PLoS One. 2014 Apr 14;9(4):e94729. PMID: 24733183

PUBLICATION

Mutations in the Drosophila ortholog of the vertebrate Golgi pH regulator (GPHR) protein disturb endoplasmic reticulum and Golgi organization and affect systemic growth.

Charroux B, Royet J.
Biol Open. 2014 Jan 15;3(1):72-80. PMID: 24357227

PUBLICATION

Mecanisms and consequences of bacteria detection by the Drosophila midgut.

Royet J, Charroux B.
Gut Microbes. 2013 May-Jun;4(3):259-63. PMID: 23633672

PUBLICATION

The Drosophila inner-membrane protein PMI controls cristae biogenesis and mitochondrial diameter.

Macchi M, El Fissi N, Tufi R, Bentobji M, Liévens JC, Martins LM, Royet J, Rival T.
J Cell Sci. 2012 Dec 21. PMID: 23264743

PUBLICATION

Peptidoglycan sensing by the receptor PGRP-LE in the Drosophila gut induces immune responses to infectious bacteria and tolerance to microbiota.

Bosco-Drayon V, Poidevin M, Boneca IG, Narbonne-Reveau K, Royet J, Charroux B.
Cell Host Microbe. 2012 Aug 16;12(2):153-65. PMID: 22901536

PUBLICATION

SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome.

Fabre A, Charroux B, Martinez-Vinson C, Roquelaure B, Odul E, Sayar E, Smith H, Colomb V, Andre N, Hugot JP, Goulet O, Lacoste C, Sarles J, Royet J, Levy N, Badens C.
Am J Hum Genet. 2012 Apr 6;90(4):689-92. doi: 10.1016/j.ajhg.2012.02.009. PMID: 22444670

PUBLICATION

Gut-microbiota interactions in non-mammals: what can we learn from Drosophila?

Charroux B, Royet J.
Semin Immunol. 2012 Feb;24(1):17-24. PMID: 22284578

PUBLICATION

Peptidoglycan recognition proteins: modulators of the microbiome and inflammation.

Royet J, Gupta D, Dziarski R.
Nat Rev Immunol. 2011 Nov 11;11(12):837-51. PMID: 22076558

PUBLICATION

Epithelial homeostasis and the underlying molecular mechanisms in the gut of the insect model Drosophila melanogaster.

Royet J.
Cell Mol Life Sci. 2011 Nov;68(22):3651-60. PMID: 21964927

PUBLICATION

Toll-8/Tollo negatively regulates antimicrobial response in the Drosophila respiratory epithelium.

Akhouayri I, Turc C, Royet* J, Charroux* B. (* co corresponding authors)
PLoS Pathog. 2011 Oct;7(10):e1002319. PMID: 22022271

PUBLICATION

Lactobacillus plantarum promotes Drosophila systemic growth by modulating hormonal signals through TOR-dependent nutrient sensing.

Storelli G, Defaye A, Erkosar B, Hols P, Royet* J, Leulier* F. (* co-senior authors)
Cell Metab. 2011 Sep 7;14(3):403-14. PMID: 21907145

PUBLICATION

The Drosophila peptidoglycan-recognition protein LF interacts with peptidoglycan-recognition protein LC to downregulate the Imd pathway.

Basbous N, Coste F, Leone P, Vincentelli R, Royet J, Kellenberger C, Roussel A.
EMBO Rep. 2011 Apr;12(4):327-33. PMID: 21372849

PUBLICATION

Polyglutamine Atrophin provokes neurodegeneration in Drosophila by repressing fat.

Napoletano F, Occhi S, Calamita P, Volpi V, Blanc E, Charroux B, Royet J, Fanto M.
EMBO J. 2011 Mar 2;30(5):945-58. PMID: 21278706

PUBLICATION

Inner-membrane proteins PMI/TMEM11 regulate mitochondrial morphogenesis independently of the DRP1/MFN fission/fusion pathways.

Rival T, Macchi M, Arnauné-Pelloquin L, Poidevin M, Maillet F, Richard F, Fatmi A, Belenguer P, Royet J.
EMBO Rep. 2011 Mar;12(3):223-30. PMID: 21274005

PUBLICATION

Lack of an antibacterial response defect in Drosophila toll-9 mutant.

Narbonne-Reveau K, Charroux B, Royet J.
PLoS One. 2011 Feb 28;6(2):e17470. PMID: 21386906

PUBLICATION

Drosophila immune response: From systemic antimicrobial peptide production in fat body cells to local defense in the intestinal tract.

Charroux B, Royet J.
Fly (Austin). 2010 Jan-Mar;4(1):40-7. PMID: 20383054

PUBLICATION

Maintaining immune homeostasis in the fly gut.

Leulier F, Royet J.
Nat Immunol. 2009 Sep;10(9):936-8. PMID: 19692992

PUBLICATION

Elimination of plasmatocytes by targeted apoptosis reveals their role in multiple aspects of the Drosophila immune response.

Charroux B, Royet J.
Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9797-802. PMID: 19482944

PUBLICATION

Bacterial detection by Drosophila peptidoglycan recognition proteins.

Charroux B, Rival T, Narbonne-Reveau K, Royet J.
Microbes Infect. 2009 May-Jun;11(6-7):631-6. PMID: 19344780

PUBLICATION

The Drosophila membrane-associated protein PGRP-LF prevents IMD/JNK pathways triggering by blocking PGRP-LC activation.

Maillet F, Bischoff V, Vignal C, Hoffmann J, Royet J.
Cell Host Microbe. 2008 May 15;3(5):293-303. PMID: 18474356

PUBLICATION

Crystal structure of Drosophila PGRP-SD suggests binding to DAP-type but not lysine-type peptidoglycan. Molecular Immunology.

Leone P, Bischoff V, Kellenberger C, Hetru C, Royet J, Roussel A.
Mol Immunol. 2008 May;45(9):2521-30. PMID: 18304640

PUBLICATION

Peptidoglycan recognition proteins: pleiotropic sensors and effectors of antimicrobial defences.

Royet J, Dziarski R.
Nat Rev Microbiol. 2007 Apr;5(4):264-77. PMID: 17363965

PUBLICATION

Downregulation of the Drosophila Immune Response by Peptidoglycan-Recognition Proteins SC1 and SC2.

Bischoff V, Vignal C, Duvic B, Boneca IG, Hoffmann JA, Royet J.
PLoS Pathog. 2006 Feb;2(2):e14. PMID: 16518472

PUBLICATION

Sensing and signaling during infection in Drosophila.

Royet J, Reichhart JM, Hoffmann JA.
Curr Opin Immunol. 2005 Feb;17(1):11-7. PMID: 15653304

PUBLICATION

Infectious non-self recognition in invertebrates: lessons from Drosophila and other insect models.

Royet J.
Mol Immunol. 2004 Nov;41(11):1063-75. PMID: 15476918

PUBLICATION

Function of the drosophila pattern-recognition receptor PGRP-SD in the detection of Gram-positive bacteria.

Bischoff V, Vignal C, Boneca IG, Michel T, Hoffmann JA, Royet J.
Nat Immunol. 2004 Nov;5(11):1175-80. PMID: 15448690

PUBLICATION

Drosophila melanogaster innate immunity: an emerging role for Peptidoglycan Recognition Proteins in bacteria detection.

Royet J.
Cell Mol Life Sci. 2004 Mar;61(5):537-46. PMID: 15004693

PUBLICATION

Toll-dependent and Toll-independent immune responses in Drosophila.

Imler, J. L., Ferrandon, D., Royet, J., Reichhart, J. M., Hetru, C., and Hoffmann, J. A.
J Endotoxin Res. 2004;10(4):241-6. PMID: 15373968

PUBLICATION

Dual activation of the Drosophila Toll pathway by two Pattern Recognition Receptors.

Gobert V, Gottar M, Matskevich AA, Rutschmann S, Royet J, Belvin M, Hoffmann JA, Ferrandon D.
Science. 2003 Dec 19;302(5653):2126-30. PMID: 14684822

PUBLICATION

Detection of peptidoglycans by NOD proteins.

Royet J, Reichhart JM.
Trends Cell Biol. 2003 Dec;13(12):610-4. PMID: 14624838

PUBLICATION

Silencing of Toll pathway components by direct injection of double-stranded RNA into Drosophila adult flies.

Goto A, Blandin S, Royet J, Reichhart JM, Levashina EA.
Nucleic Acids Res. 2003 Nov 15;31(22):6619-23. PMID: 14602922

PUBLICATION

Notch signaling controls lineage specification during Drosophila larval hematopoiesis.

Duvic, B., Hoffmann, J. A., Meister, M., and Royet, J.
Curr Biol. 2002 Nov 19;12(22):1923-7. PMID: 12445385

PUBLICATION

The Drosophila immune response against Gram-negative bacteria is mediated by a peptidoglycan recognition protein.

Gottar M, Gobert V, Michel T, Belvin M, Duyk G, Hoffmann JA, Ferrandon D, Royet J.
Nature. 2002 Apr 11;416(6881):640-4 PMID: 11912488

PUBLICATION

Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein.

Michel T, Reichhart JM, Hoffmann JA, Royet J.
Nature. 2001 Dec 13;414(6865):756-9 PMID: 11742401

Members more

Bernard Charroux   Leopold Kurz   Annelise Viallat Lieutaud  
Julien Royet
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Julien Royet

University lecturer

Julien is a professor of Cell biology and head of the Development and Immunology Master Program at Aix Marseille University. He is working on the mechanisms of innate immunity in Drosophila melanogaster. He received his PhD degree from the University of Lyon, France, and completed postdoctoral training at the University of Pennsylvania, Philadelphia, USA, and at the European Molecular Biology Laboratory in Heidelberg, Germany. From 1999 to 2005, he worked at the Institut de Biologie Moléculaire et Cellulaire in Strasbourg, France.

Bernard Charroux
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Bernard Charroux

Researcher

Bernard, CNRS researcher, joined the team in January 2007 coming from the field of developmental biology. Bernard has recently devoted his time in understanding the mechanisms that control the complex relationship that occurs between the microbiota and the gut epithelium. His efforts are also focusing on analyzing the consequences of having a gut-associated microbiota on the physiology of the host.

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Manish Joshi

PhD student

Leopold Kurz
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Leopold Kurz

University lecturer

Leo, University lecturer, joined the lab on September 2012 coming from the field of innate immunity in C. elegans. In addition to his teaching responsibilities at the Bachelor and Master levels, Leo is trying to understand why an overactivation of the immune response can have, like in humans, detrimental effects on the fly's fitness.

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Ambra Masuzzo

PhD student

Annelise Viallat Lieutaud
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Annelise Viallat Lieutaud

Technical staff

Annelise joined the team in October 2013. Annelise graduated from the engineer school ESIL/Polytech of Marseille. She is heading the Drosophila transgenic facility at IBDM where she is developing new strategies and tools to modulate gene expression in the Drosophila model. In addition, Annelise is also our lab manager.

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Olivier Zugasti

Researcher

Alumni

  • Karine Narbonne, CR CNRS, IBDM
  • François Leulier, Group Leader, IGFL, Lyon
  • Marc Macchi, PhD Student, Postdoc Japan
  • Arnaud Defaye, PhD student
  • Melanie Bentobli, Assistant engineer, IPC, Marseille
  • Virginie Bosco-Drayon, Engineer, IPC, Marseille
  • Berra Erkosar, Postdoc, EPFL, Lausanne

Overview

Animal model organism
Biological process studied
  • Bacteria-Gut interactions
  • Mitochondria dynamics
Biological techniques
  • Genetics, RNAi screening
  • Live imaging
  • CRISPR mediated mutagenesis
  • Cell biology
  • Microarrays