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 <i>Mannheimia haemolytica</i> (<i>M. haemolytica</i>) infection by driving inflammasome signaling activation. <i>Ifi204^-/-</i> mice are more susceptible to pathogenic <i>M. haemolytica</i> 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 <i>Ifi204</i> deficiency leads to a defect in inflammasome signaling activation, and exogenous recombinant IL-18 is sufficient to rescue the susceptibility of <i>Ifi204^-/-</i> 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 <i>M. haemolytica</i>-derived genomic DNA for the inflammasome signaling response. Thus, these data highlight the requirement of IFI204 in host defense response to <i>M. haemolytica</i> infection, and reveal that IFI204 may be a potential therapeutic target for pathogen control.