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.