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