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Cell biology of inflammasome activation in macrophages infected with Francisella

Final Report Summary - INFLAFRAN (Cell biology of inflammasome activation in macrophages infected with Francisella)

The scientific goal of the project was to study an innate immune complex termed the inflammasome during infection with Francisella tularensis. Francisella tularensis is a pathogenic bacterium causing tularemia. Its virulence is linked to its ability to replicate within host cells. Indeed, following phagocytosis by macrophages, Francisella rapidly escape from the phagosome to reach the host cytosol where it can replicate to very high number.
We had previously shown that activation of the inflammasome during Francisella infection was due to recognition of bacterial DNA by the inflammasome receptor AIM2. AIM2 then interacts with the inflammasome adaptor ASC leading to caspase-1 activation. In this project, by studying the different inflammasome components at the molecular and cellular levels, Thomas Henry's team discovered that AIM2 and ASC in addition to their well-characterized ability to activate caspase-1 can also activate caspase-8 to trigger apoptosis. This discovery was important since host cell death is a very important mechanism to fight bacteria replicating intracellularly by removing the bacterial replicative niche.
Importantly, the team validated this finding in vivo in a mouse model of tularemia. For the first time, they described that bioactive IL-18 could be generated in vivo in a caspase-1-independent manner. They further showed that in this experimental system, IL-18 activates innate immune lymphocytes (NK cells) to produce IFN-γ. As this cytokine is the most important signal to fight against intracellular pathogen, this finding is important. These studies illustrate the robustness of the innate immune system, which has several parallel pathways to fight microbes, which have often evolve mechanisms to counteract specific innate immune pathways.
This last point was also illustrated by the researchers who discovered -in a work still in progress-a virulence factor of Francisella, which inhibits Toll-like Receptor 2 signaling (another innate immune signaling pathway).
The goal of this project (Re-integration grant) was also to re-integrate the researcher namely Thomas Henry-after a four years post-doctoral training in the USA- in the European scientific community and ensure the development of his research career. On these points, the project is also a success. Indeed Thomas Henry has obtained a permanent research position at Inserm. He is now leading an Inserm research team of 14 people in the Centre International de Recherche en Infectiologie. He has managed to attract excellent scientists. He obtained a number of grants (including an ERC starting grant) allowing him to sustain the research of his team and the employment of his staff members. In the 2011-2015 period, he has published 23 papers some in journal with high impact factors.
In addition to the transfer of knowledge associated with his publications and his communications in different research institutes and at several international conferences, Thomas Henry has been transferring his knowledge to students through teaching. In addition, he has been communicating on his science to the general public through publications of a book chapter and several reviews in French aimed at medical doctors or the general public.
More details can be found on the website of the Centre International de Recherche en Infectiologie at : http://ciri.inserm.fr/en/