Soutenance de Thèse de Devon CONTI

Présentation

PhD defense: Tripartite interplay between host, bacteria and bacteriophages in pathogen-driven gut inflammation – Devon Conti

Summary

This thesis explores the dynamic interactions between host, bacteria, and phages, in the context of intestinal infections by Clostridioides difficile, Citrobacter rodentium, and extraintestinal pathogenic Escherichia coli (ExPEC) ST131. We leveraged the gnotobiotic mouse model OMM¹² to characterise these interactions.

We developed a unique, highly reproducible, chronic infection model for C. difficile (until 20 days) without the need for antibiotic pre-treatment. CDI caused significant inflammation, tissue destruction as well as transient perturbations in gut bacterial abundances. This model represents a valuable platform for future studies into C. difficile asymptomatic carriage as well as investigations of gut-related evolutionary dynamics.

C. rodentium introduction into OMM¹² mice exhibited a distinct ‘peak and persistence’ colonization kinetics, which represents an intermediary phenotype between conventional and germ-free mice. We extensively characterised C. rodentium colonization in terms of microbiota composition analysis and host response. We observed that inflammation and colonization peaked by day 10. Thereafter, by day 20 colonization dropped by 2-logs, yet C. rodentium persisted and inflammation was resolved. We sought to characterise this unique persistence. We found that OMM¹² mice pre-colonized by an Escherichia coli strain did not prevent C. rodentium infection but cleared this pathogen in 50% of mice from day 17. We identified and experimentally demonstrated that a bacteriocin (colicin-Y) is mediating C. rodentium clearance by direct competition and enhancement of the host immune response.

Finally, we sought to develop a dual-strike therapeutic approach to target the gut reservoir of a multidrug resistant E. coli ST131 isolate by combining an intracellular host-targeting drug C910, shown to reduce tissue replication, with a phage cocktail to selectively target luminal ST131. We found both in vitro and ex vivo that the combined treatment contributed to a dramatic reduction of ST131 in luminal and tissue niches.

Overall, these studies demonstrate that gnotobiotic murine models can be leveraged to study tripartite interactions between host, bacteria and phages and to decipher the molecular mechanisms involved.

Localisation

Bâtiment: François Jacob
Adresse: Institut Pasteur, Rue du Docteur Roux, Paris, France

Un petit guide pour l'utilisation de la recherche avancée :

Conférenciers

Présentation

Partenaires

Localisation