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Published on December 14, 2018 | Updated on December 14, 2018
INTRACELL-X-EVO Project
Experimental evolution of an intracellular bacterium within its host cell
Co-leaders : Thomas Henry (CIRI) & Eric Tannier (LBBE)
Francisella tularensis, the agent of tularemia, is a bacterium replicating within the macrophage cytosol. While the antibacterial responses against bacteria replicating within a vacuole are well understood, the antibacterial responses taking place in the host cytosol are still poorly understood. In this project, we will conduct an experimental evolution approach to understand how the pathogen evolves in relation with the host immune response to replicate within the cytosol of eukaryotic cells. More specifically, we will repeatedly infect macrophages with a population of Francisella novicida until this population has undergone 1000 generations.
The cause of the expected gain in fitness will be identified thanks to whole genome sequencing. Several independent lines will be evolved either in macrophages proficient or deficient for two cytosolic innate immune responses namely the type I IFN and the inflammasome pathways. In addition, the in cellulo experimental evolution will be compared to in broth experimental evolution. Importantly, we will not only focus on point mutations and small indels but we will also look for large genomic rearrangements thanks to the development of novel algorithms to identify structural mutations. Contribution of each individual mutations/rearrangements to the gain of fitness will be evaluated experimentally in regards to specific cytosolic innate immune responses. This project should lead to the identification of key virulence genes controlling bacterial replication in the tug of war with the cytosolic innate immune responses. Furthermore, it should give us insights onto the adaptive mutations required for the increased association of an intracellular bacterium with its host.
Co-leaders : Thomas Henry, team "Inflammasome et infections bactériennes" (CIRI) & Eric Tannier, team "Bioinformatique et Génomique Evolutive" (LBBE).
The cause of the expected gain in fitness will be identified thanks to whole genome sequencing. Several independent lines will be evolved either in macrophages proficient or deficient for two cytosolic innate immune responses namely the type I IFN and the inflammasome pathways. In addition, the in cellulo experimental evolution will be compared to in broth experimental evolution. Importantly, we will not only focus on point mutations and small indels but we will also look for large genomic rearrangements thanks to the development of novel algorithms to identify structural mutations. Contribution of each individual mutations/rearrangements to the gain of fitness will be evaluated experimentally in regards to specific cytosolic innate immune responses. This project should lead to the identification of key virulence genes controlling bacterial replication in the tug of war with the cytosolic innate immune responses. Furthermore, it should give us insights onto the adaptive mutations required for the increased association of an intracellular bacterium with its host.
Co-leaders : Thomas Henry, team "Inflammasome et infections bactériennes" (CIRI) & Eric Tannier, team "Bioinformatique et Génomique Evolutive" (LBBE).
Collaborative teams: Dominique Schneider, team "Adaptation et pathogénie des Microorganismes" (La Tronche).
Project duration : 3 years
Financing : Post-doctoral fellowship & consumable money
Post-doctoral fellow : Claire Lays
Financing : Post-doctoral fellowship & consumable money
Post-doctoral fellow : Claire Lays