Dominique FERRANDON, Directeur de recherches (DR1-CNRS), Responsable Équipe : Relations Hôte-Pathogène et Résilience, au sein de l'unité de recherche M3I (Modèles insectes d'immunité innée UPR9022) à l'IBMC de Strasbourg (Institut de Biologie Moléculaire et Cellulaire).
Expertise dans les mécanismes moléculaires permettant à un hôte et un micro-organisme de s'adapter l'un à l'autre, sur le modèle drosophile, plus particulièrement dans purge intestinale, un mécanisme de protection de l'épithélium intestinal aux infections bactériennes et aux xénobiotiques.
30 octobre 2025 à 10h30, salle Ruffié batiment C IRSD et retransmission TEAMS
ABSTRACT
The study of Drosophila innate immunity has been started by the identification of effector antibiotic molecules known as antimicrobial peptides (AMPs). The genetic analysis of the induction of the expression of the cognate genes delineated two intracellular signaling pathways, the Toll and Immune deficiency pathways that regulate the activation of NF-kB type transcription factors. Whereas the IMD pathway is activated at the level of the cell membrane by a receptor that binds to the peptidoglycan found in Gram-negative bacteria, the Toll pathway is actually activated through extracellular proteolytic cascades initiated upon sensing the LYS-type peptidoglycan found in many Gram-positive bacterial species and also upon sensing the ß-(1-3) glucans found in the fungal cell wall. Alternatively, the baiting of microbial proteases also leads to Toll pathway activation. These findings define the humoral systemic immune response, a major arm of Drosophila innate immunity, a scheme that has been derived mostly using nonpathogenic bacteria. In addition, there are also local immune responses, for instance those that take place in the intestinal epithelium.
Whereas we had identified several key genes of the immune response in genetic screens that monitored the induction level of AMP genes, we ushered a novel era by launching large-scale screens using the survival to infection as a less-biased read-out of the host defense. A major lesson learned in these screens is that most of the hits do not correspond to genes required for resistance to infections, that is that the gene products are not required to attack the invading pathogens. Rather, they allow the host to endure, and to some extent to repair damages exerted by virulence factors secreted by pathogens or caused by the host’s own immune response, a concept that I name resilience, which is also known as disease tolerance. It actually corresponds to the intersection between microbial pathogenesis and physiological homeostasis, which encompasses a variety of mechanisms, some of them totally unexpected.
For instance, we have discovered that the attack of the intestinal epithelium by a pore-forming toxin secreted by the Gram-negative entomopathogen Serratia marcescens triggers the extrusion of the apical cytoplasm of enterocytes, which contains damaged organelles, invading bacteria and likely toxins. This results in a thin epithelium within a couple of hours, which ultimately regains its original thickness, an evolutionarily-conserved epithelial behavior.
A large body of work has been devoted to the study of host defenses against fungal infections with the initial characterization of infections by the entomopathogenic fungus Metarhizium robertsii or the opportunistic pathogen Aspergillus fumigatus. Interestingly, we have discovered that the Toll-mediated host defense against the latter pathogen is not through resistance but through resilience: a variety of Toll effectors mediate protection against the action or effects of secreted virulence factors such as the neurotoxin verruculogen or ribotoxin restrictocin mycotoxins. Amazingly, even though the Toll pathway likely regulates the induction of hundreds of genes, just deleting ten Bomanin genes at the 55C locus suffices to phenocopy the Toll pathway mutant phenotype of sensitivity to Gram-positive bacterial, pathogenic monomorphic and dimorphic yeasts, and to filamentous fungi. For instance, one such gene product, BomT1, is required for resistance against Enterococcus faecalis, resilience against M. robertsii infection, and protection against restrictocin. We have also identified other effectors that together protect against a variety of secreted virulence factors such as Outer Membrane Vesicles, and the metalloproteases they carry, from Pseudomonas aeruginosa and Serratia marcescens, an enterocin from E. faecalis, and a neuromycotoxin from M. robertsii. We thus need to learn a new grammar to understand how host secreted peptides manage to counteract the action of secreted virulence factors of prokaryotic or eukaryotic origins.
Finally, the Drosophila model is especially well-suited to dissect the host-pathogen equation from the viewpoint of both pathogen and host. We thus have recently discovered that P. aeruginosa needs to adapt to its host by changing its shape prior to being virulent. An elongated shape allows the pathogen to resist the action of three families of AMPs. Mechanistically, P. aeruginosa shape change occurs upon sensing host-derived N-acetyl-glucosamine, which activates the type IV pili-associated PilJ chemosensory system and cAMP signaling that together mediate the elongation of the bacteria in vivo.