The transcription factor IRF1 and guanylate-binding proteins target AIM2 inflammasome activation by Francisella infection

Inflammasomes are critical for mounting host defense against pathogens. The molecular mechanisms controlling activation of the AIM2 inflammasome in response to different cytosolic pathogens is unclear. Here, we show that the transcription factor IRF1 is the upstream molecule leading to AIM2 inflammasome activation during Francisella novicida infection, whereas engagement of the AIM2 inflammasome by mouse cytomegalovirus or transfected dsDNA did not require IRF1. F. novicida infection detected by the cGAS-STING pathway induces type I interferon-dependent expression of IRF1, which drives the expression of guanylate-binding proteins (GBPs) leading to intracellular bacterial killing and DNA release. These results reveal a specific requirement for IRF1 and GBPs in the liberation of DNA for AIM2 sensing depending on the pathogen encountered by the cell.