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.
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.
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.
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.
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
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
July 18th, 2017
Oligopeptide Transporters of the SLC15 Family Are Dispensable for Peptidoglycan Sensing and Transport in Drosophila.
March 7th, 2017
Peptidoglycan sensing by octopaminergic neurons modulates Drosophila oviposition.
January 13th, 2017
Inhibition of a NF-κB/Diap1 Pathway by PGRP-LF Is Required for Proper Apoptosis during Drosophila Development
January 8th, 2016
Bacteria sensing mechanisms in Drosophila gut: Local and systemic consequences.
January 1st, 2016
Tissue-Specific Regulation of Drosophila NF-x03BA;B Pathway Activation by Peptidoglycan Recognition Protein SC.
April 14th, 2014
Drosophila Microbiota Modulates Host Metabolic Gene Expression via IMD/NF-κB Signaling.
November 23rd, 2013
Mutations in the Drosophila ortholog of the vertebrate Golgi pH regulator (GPHR) protein disturb endoplasmic reticulum and Golgi organization and affect systemic growth.
June 4th, 2013
Mecanisms and consequences of bacteria detection by the Drosophila midgut.
December 21st, 2012
The Drosophila inner-membrane protein PMI controls cristae biogenesis and mitochondrial diameter.
August 16th, 2012
Peptidoglycan sensing by the receptor PGRP-LE in the Drosophila gut induces immune responses to infectious bacteria and tolerance to microbiota.
April 1st, 2012
SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome.
February 1st, 2012
Gut-microbiota interactions in non-mammals: what can we learn from Drosophila?
November 11th, 2011
Peptidoglycan recognition proteins: modulators of the microbiome and inflammation.
November 1st, 2011
Epithelial homeostasis and the underlying molecular mechanisms in the gut of the insect model Drosophila melanogaster.
October 1st, 2011
Toll-8/Tollo negatively regulates antimicrobial response in the Drosophila respiratory epithelium.
September 7th, 2011
Lactobacillus plantarum promotes Drosophila systemic growth by modulating hormonal signals through TOR-dependent nutrient sensing.
April 1st, 2011
The Drosophila peptidoglycan-recognition protein LF interacts with peptidoglycan-recognition protein LC to downregulate the Imd pathway.
March 2nd, 2011
Polyglutamine Atrophin provokes neurodegeneration in Drosophila by repressing fat.
March 1st, 2011
Inner-membrane proteins PMI/TMEM11 regulate mitochondrial morphogenesis independently of the DRP1/MFN fission/fusion pathways.
February 28th, 2011
Lack of an antibacterial response defect in Drosophila toll-9 mutant.
January 1st, 2010
Drosophila immune response: From systemic antimicrobial peptide production in fat body cells to local defense in the intestinal tract.
September 1st, 2009
Maintaining immune homeostasis in the fly gut.
June 16th, 2009
Elimination of plasmatocytes by targeted apoptosis reveals their role in multiple aspects of the Drosophila immune response.
May 1st, 2009
Bacterial detection by Drosophila peptidoglycan recognition proteins.
May 15th, 2008
The Drosophila membrane-associated protein PGRP-LF prevents IMD/JNK pathways triggering by blocking PGRP-LC activation.
May 1st, 2008
Crystal structure of Drosophila PGRP-SD suggests binding to DAP-type but not lysine-type peptidoglycan. Molecular Immunology.
April 1st, 2007
Peptidoglycan recognition proteins: pleiotropic sensors and effectors of antimicrobial defences.
February 1st, 2006
Downregulation of the Drosophila Immune Response by Peptidoglycan-Recognition Proteins SC1 and SC2.
February 1st, 2005
Sensing and signaling during infection in Drosophila.
November 1st, 2004
Infectious non-self recognition in invertebrates: lessons from Drosophila and other insect models.
November 1st, 2004
Function of the drosophila pattern-recognition receptor PGRP-SD in the detection of Gram-positive bacteria.
March 1st, 2004
Drosophila melanogaster innate immunity: an emerging role for Peptidoglycan Recognition Proteins in bacteria detection.
January 1st, 2004
Toll-dependent and Toll-independent immune responses in Drosophila.
December 19th, 2003
Dual activation of the Drosophila Toll pathway by two Pattern Recognition Receptors.
December 1st, 2003
Detection of peptidoglycans by NOD proteins.
November 15th, 2003
Silencing of Toll pathway components by direct injection of double-stranded RNA into Drosophila adult flies.
November 19th, 2002
Notch signaling controls lineage specification during Drosophila larval hematopoiesis.
April 11th, 2002
The Drosophila immune response against Gram-negative bacteria is mediated by a peptidoglycan recognition protein.
December 13th, 2001