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DynPhages

Bacteriophage Genome Dynamics

Bacteriophages have been evolving on Earth for billions of years, and are found everywhere. The Bacteriophage genome dynamics team (DynPhage) wants to decipher molecular mechanisms at the root of their ecological success, and to evolve them as potent alternatives to antibiotics against pathogens such as Enterococcus faecium, Escherichia coli and Pseudomonas aeruginosa.

Marie-Agnès PETIT

Research axis

  • Genome evolution by recombination - DynPhagesPhages are among the oldest and most abundant biological entities on Earth, displaying remarkable genetic diversity. This is partly due to the fact that ~60% of phages code for particular recombination systems that are highly efficient and diverse. Among this diversity of viral recombinases, three superfamilies have been recognized and named after the fold of their best-characterized member: RAD52-like, Gp2.5-like and RAD51/RecA-like. However, the diversity of proteins interacting with these recombinases is at the origin of highly diversified molecular mechanisms of recombination in phages, which are still poorly understood. The team is interested in identifying the partners of different phage recombinases and characterizing the mechanism of recombination in vitro and in vivo. Current studies focus on the RecT/Gam pair of the Gally phage and the Sak4/SSB pair of the HK620 phage, both infecting Escherichia coli.
  • In addition to their long-term evolutionary role, phage recombinases can also confer short-term advantages in the life cycle of their cognate phage. This is thought to result from their involvement in DNA replication, although this function is not well conserved and still poorly understood even in model phages. We are measuring the effect of deletion of these recombination modules on host DNA replication in order to identify the steps involving them and understand their role in phage genome synthesis.
  • The use of the lambda recombination module (λred) in genome engineering has greatly simplified the way in which the genome of E. coli and related strains can be modified. However, the use of this module in other bacterial species is little or non-existent. This is due to the involvement of other proteins in the recombination mechanism, notably host proteins. The team is looking for these host proteins, which will enable us to extend the spectrum of action of phage recombination modules effective in E. coli to other species.
  • Ecological impact of prophages - DynPhagesIn an ecosystem such as the intestinal microbiota, most bacteria host prophages. It is suspected that metabolites from other bacteria, from the diet or from the host may act as prophage inducers, although at present little is known on the topic. The team is exploring which signals could lead to prophage induction, using mostly germ-free mouse hosting simplified microbiota. Part of the project is conducted in collaboration with Dr Debarbieux (I. Pasteur).
  • The team’s long-standing expertise in temperate phages of Escherichia coli has also led us to characterize an atypical induction of the lytic cycle in the adherent invasive Escherichia coli strain LF82, in collaboration with Dr Espeli (Collège de France, ANR Persist3Rs). This strain hosts five prophages, and its most active prophage Gally has a peculiar behavior inside macrophages: it is repressed under conditions inducing the SOS response. The mechanism behind this original repression mechanism is under study.
  • Prophage induction can also be apprehended through virome analyses, although methodological developments are still needed. Our expertise in virome sequencing and analysis has opened collaborations with several INRAE teams (Muse@Micalis, Dr De Paepe, NutriPhage@Micalis, Dr Pfeifer, Sayfood, Dr Dugat-Bony; Pathologie des Plantes, Dr Torres-Barcelo; PROSE, Dr Bize), a French laboratory (Hopital Saint-Antoine and Université Paris-Sorbonne, Dr De Sordi), a French company (MaaT Pharma), as well as through a Joint Program Initiative project, with Canada (U. Laval, Dr Moineau) and Denmark (U. Copenhagen, Dr Nielsen, COPSAC clinic, Dr Shah).
  • The ecological impact of two other prophages has also been studied in the framework of collaborations where our team had a support function: behavior of an E. coli strain hosting prophage 933W in germ-free mice (collaboration with Dr Bentancor, Buenos Aires), and study of an original induction mechanism for a prophage of Streptomyces ambofaciens (collaboration with Dr Bury-Moné, I2BC, France).

Phages against antibioresistance - DynPhages

For bacterial pathogens exhibiting ever increasing levels of resistance to antibiotics, phages are becoming a serious alternative for treatment.

  • We have isolated and characterized virulent phages against clinical isolates of Enterococcus faecalis and E. faecium, pathogens listed by the WHO for which new drugs are urgently needed, in collaboration with Dr Serror and Dr Repoila (CPE@Micalis), and Dr Cattoir (U. Rennes, INSERM). Facing the fact most natural phages infect only few strains within a given species, we have developed expertise in evolution experiments to enlarge phage host range.
  • With a view to combating another opportunistic pathogen, the team collaborated with Phaxiam (previously Pherecydes Pharma) and explored phage-host relationships for a set of Pseudomonas aeruginosa infecting virulent phages.
  • Using phages to fight against antibioresistance requires that their genomes be annotated to the best of our knowledge. The team has been contributing to optimize tools such as PHROGS (with Dr Enault, U. Clermont Auvergne) for phage genome annotation and classification.
  • The full efficiency of bacterial eradication by phages relies on their capacity to lyse every bacteria they infect. We are currently exploring an understudied phage cycle named pseudolysogeny, whereby virulent phages halt their lytic cycle, being maintained inside their host in a semi-dormant state, not unlike temperate phages.

Team members

Caroline HENROT

  • PhD student

Olivier SON

  • Technician

Julien LOSSOUARN

  • Engineer

Elisabeth MONCAUT

  • Engineer

Benoît LEROUGE

  • PhD student

François LECOINTE

  • Scientist

Marie-Agnès PETIT

  • Scientist
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