IFI204 Restricts Mannheimia haemolytica Pneumonia via Eliciting Gasdermin D-Dependent Inflammasome Signaling

Host innate immunity is crucial for orchestrating a protective response against dangerous pathogens. Herein, we demonstrate that interferon-inducible protein (IFI204), a DNA sensor, is implicated in protection against pulmonary pathogenic Mannheimia haemolytica (M. haemolytica) infection by driving inflammasome signaling activation. Ifi204^-/- mice are more susceptible to pathogenic M. haemolytica infection compared with their wild-type (WT) counterparts, with decreased survival rates, extensive lung architecture destruction, exacerbated inflammatory cells infiltration, and more bacterial colonization. In vivo and in vitro findings elucidate that Ifi204 deficiency leads to a defect in inflammasome signaling activation, and exogenous recombinant IL-18 is sufficient to rescue the susceptibility of Ifi204^-/- mice. Inflammasome signaling downstream of IFI204 facilitates early bacterial killing and clearance. Mechanistically, IFI204 promotes gasdermin D (GSDMD)-dependent inflammasome activation, and GSDMD is required for IFI204-mediated host defense. Notably, IFI204 detects pathogenic M. haemolytica-derived genomic DNA for the inflammasome signaling response. Thus, these data highlight the requirement of IFI204 in host defense response to M. haemolytica infection, and reveal that IFI204 may be a potential therapeutic target for pathogen control.