Opposing roles of AIM2 inflammasome and type I interferon signaling in Francisella infection

Abstract

Abstract Inflammasomes are crucial for mediating protection against microbial infection. Type I interferon (IFN) signaling is required for driving activation of the AIM2 inflammasome in macrophages in response to infection by Francisella tularensis subspecies novicida (F. novicida). Here, we showed that compared with infected wild-type mice, mice lacking the type I IFN receptor IFNAR2 exhibited increased resistance towards F. novicida infection, whereas mice lacking AIM2 were more susceptible. In addition, mice lacking IRF9, a core component of IFN-stimulated gene factor 3 that transduces type I IFN signaling, showed increased resistance following infection. These results suggested that while type I IFN signaling and AIM2 were essential for activation of the Francisella-induced inflammasome in macrophages, these components have strikingly contrasting effects in vivo. Importantly, we found that mice lacking both AIM2 and IFNAR2 were more resistant than infected wild-type mice and mice lacking AIM2. Taken together, we identified type I IFN signaling as a dominant regulator of anti-microbial activity during F. novicida infection in vivo even in the absence of AIM2 responses.