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Deciphering cytosolic antibacterial immunity: from triggering bacteriolysis to Aim2 inflammasome activation

Final Report Summary - CYTOBACLYSIS (Deciphering cytosolic antibacterial immunity: from triggering bacteriolysis to Aim2 inflammasome activation)

The main objective of this project was to identify the mechanisms leading to the killing of bacteria replicating within the cytosol of host cells. This question is of paramount importance since it is dealing with understanding the natural antibiotic mechanisms of human cells at a time where we see an increase in the number of antibiotic resistance mechanisms. Through a large genetic screen, we identified two proteins from the family of "Guanylate Binding Proteins" as key antibacterial proteins from the host cytosol. We demonstrated that these host proteins target a cytosolic-replicating pathogenic bacterium (Francisella tularensis) in the host cytosol and lyse this bacterium. Importantly, this host-mediated bacteriolysis triggers downstream innnate immune responses since GBP-mediated bacteriolysis is associated with the release of genomic bacterial DNA in the host cytosol, which is then recognized by the AIM2 inflammasome. The relevance of this antibiotic mechanism was demonstrated both in vivo in a mouse model of tularemia (a disease caused by Francisella tularensis) and in primary human cells. While we have now identified this antibiotic mechanisms in human cells, it remains to be understood how highly virulent bacteria escape this mechanism and whether we can increase its efficiency to help the immune system to combat intracellular pathogens.