TEAM

Host pathogen interaction in the Drosophila model

Group leader : J. Royet

Using the Drosophila model to dissect the molecular mechanisms by which the nervous system of eukaryotes detects the environmental bacteria and how these bacteria-neuron interactions, in turn, modify the behavior of the host.

FOR BEGINNERS

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

Animals live in an environment populated by microorganisms, most of which are harmless. However, because some of these microbes are pathogenic and pose a threat to the integrity of the host, animals have, over times, acquired an immune system that eliminates pathogenic invaders. In addition to strategies intended to the direct eradication of the causal agent of infection, animals, including humans, adopt behaviors, grouped under the generic term of behavioral immunity, aimed at reducing the impact of infection on themselves or on their offspring. While the molecular mechanisms by which microorganisms are eliminated by the immune system are known with great precision, the mediators of behavioral immunity remain largely ignored.
We are taking advantages on the power of Drosophila genetics to dissect the molecular mechanisms by which non-immune, neuronal or glial cells detect bacteria and how this detection triggers changes in host behavior and physiology. Studies showing that mice with impaired ability to detect bacteria exhibit abnormal behavior suggest that our project will have implications beyond the Drosophila model, namely in mammals.

A rare case of smiling mitochondria !

FOR SPECIALISTS

Since eukaryotes live in an environment heavily contaminated by microorganisms, it is not surprising that they have forged, over the times, complex and intimate relationships between them. It is also expected that eukaryotes have developed mechanisms to perceive the presence of bacteria and to adapt their immune response, their physiological status or even their comportment accordingly. Bacteria can interact with the nervous system of eukaryotes, either for the benefit of the microbe that alters the host’s comportment or to the advantages of the host that adapts its behavior to the infection. However, the molecules underlying the dialog between bacteria and neurons of their hosts are, in most cases, not identified and, when they are, their mode of action is poorly understood.

Our goal is to use the latest genetic, imaging and bio-informatics technologies to identify the players and the molecular networks that govern this peculiar prokaryotes-eukaryotes dialog. We performed our research in the genetically amenable Drosophila model whose genome is easily edited using the CRISPR/Cas9 technology and in which most fundamental biological processes are shared with mammals.

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

One aspect of this research deals with one specific bacteria cell wall component, called peptidoglycan (PGN). PGN is a major constituent of the bacterial call wall. When present it the host body cavity, it elicits a range of reactions in higher animals, the principal being the activation of the antibacterial immune response upon its detection by host sentinel proteins. Improper detection of microbiota-derived PGN by the NOD proteins leads to the onset of Crohn disease, one of the most prevalent inflammatory bowel diseases in humans. Previous works in the lab, has demonstrated that in infected flies, bacteria-derived PGN can be sensed by some neurons of the fly central nervous system. This PGN-neuron interaction induces a series of behavioral changes which reduce the consequences of infection on the host. We demonstrated that PGN is directly detected by very few brain octopaminergic neurons. In turn, these neurons inhibit the egg-laying behavior of infected females. We have identified proteins expressed in these neurons which enable them to sense PGN and to modulate its effects on neurons. Interestingly, these proteins that belong to the NF-ΚB pathway are the same than those required in immune cells to trigger an antibacterial response upon PGN detection. Some of these proteins are not only expressed in neurons regulating oviposition but also in external sensory neurons such as gustatory sensilla suggesting that PGN-neurons interactions also concern higher functions of the flies, such as feeding.

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

Hence our lab takes advantage of the power of Drosophila genetics to dissect at the molecular level, the mechanisms by which neurons are sensing PGN and how this interaction is translated into behavioral changes for the host. Recent results showing that PGN sensors and transporters are expressed in the mouse brain and that mice deficient in PGN-sensing proteins present social behavioral alterations let us believe that the mechanisms that we study could be also exist in mammals.


Selected publications

PUBLICATION

Gut bacteria-derived peptidoglycan induces a metabolic syndrome-like phenotype via NF-κB-dependent insulin/PI3K signaling reduction in Drosophila renal system

Olivier Zugasti, Raphäel Tavignot, Julien Royet
Sci Rep . 2020 Aug 24;10(1):14097. doi: 10.1038/s41598-020-70455-7. PMID: 32839462

PUBLICATION

Drosophila Aversive Behavior toward Erwinia carotovora carotovora Is Mediated by Bitter Neurons and Leukokinin

Bernard Charroux, Fabrice Daian, Julien Royet
iScience . 2020 May 12;23(6):101152. doi: 10.1016/j.isci.2020.101152. PMID: 32450516

PUBLICATION

Uridine Catabolism Breaks the Bonds of Commensalism

Manish Joshi, Julien Royet
Cell Host Microbe . 2020 Mar 11;27(3):312-314. doi: 10.1016/j.chom.2020.02.008. PMID: 32164840

PUBLICATION

Peptidoglycan-dependent NF-κB activation in a small subset of brain octopaminergic neurons controls female oviposition

Ambra Masuzzo, Gérard Manière, Annelise Viallat-Lieutaud, Émilie Avazeri, Olivier Zugasti, Yaël Grosjean, C Léopold Kurz, Julien Royet
Elife . 2019 Oct 29;8:e50559. doi: 10.7554/eLife.50559 PMID: 31661076

PUBLICATION

Lipid Catabolism Fuels Drosophila Gut Immunity

Masuzzo A, Royet J.
Cell Host Microbe. 2018 Mar 14;23(3):288-290. doi: 10.1016/j.chom.2018.02.006. PMID: 29544092

PUBLICATION

Cytosolic and Secreted Peptidoglycan-Degrading Enzymes in Drosophila Respectively Control Local and Systemic Immune Responses to Microbiota

Bernard Charroux, Florence Capo, C Léopold Kurz, Sabine Peslier, Delphine Chaduli, Annelise Viallat-Lieutaud, Julien Royet
Cell Host Microbe . 2018 Feb 14;23(2):215-228.e4. doi: 10.1016/j.chom.2017.12.007. Epub 2018 Feb 1. PMID: 29398649

PUBLICATION

Drosophila larvae food intake cessation following exposure to Erwinia contaminated media requires odor perception, Trpa1 channel and evf virulence factor

Seydou Keita, Ambra Masuzzo, Julien Royet, C Leopold Kurz
J Insect Physiol . 2017 May;99:25-32. doi: 10.1016/j.jinsphys.2017.02.004. Epub 2017 Feb 21. PMID: 28232220

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

PUBLICATION

Peptidoglycan-dependent NF-κB activation in a small subset of brain octopaminergic neurons controls female oviposition

Masuzzo A, Manière G, Viallat-Lieutaud A, Avazeri É, Zugasti O, Grosjean Y, Kurz CL, Royet J.
Elife. 2019 Oct 29;8. pii: e50559. doi: 10.7554/eLife.50559. PMID: 31661076

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

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

Emilie Avazeri Florent Fioriti Manish Joshi Leopold Kurz Ambra Masuzzo Martina Montanari Annelise Viallat Lieutaud Olivier Zugasti
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.

Emilie Avazeri
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Emilie Avazeri

Technical staff

Florent Fioriti
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Florent Fioriti

PhD student

Manish Joshi
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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.

Ambra Masuzzo
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Ambra Masuzzo

PhD student

Martina Montanari
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Martina Montanari

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.

Olivier Zugasti
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Olivier Zugasti

Researcher

Overview

Animal model organism
Biological process studied
  • Host-pathogen interactions
  • Neuro-immunity