Gasdermin D independent canonical inflammasome responses cooperate with caspase-8 to establish host defense against gastrointestinal Citrobacter rodentium infection.

Citrobacter rodentium is an enteropathogen that causes intestinal inflammatory responses in mice reminiscent of the pathology provoked by enteropathogenic and enterohemorrhagic Escherichia coli infections in humans. C. rodentium expresses various virulence factors that target specific signaling proteins involved in executing apoptotic, necroptotic and pyroptotic cell death, suggesting that each of these distinct cell death modes performs essential host defense functions that the pathogen aims to disturb. However, the relative contributions of apoptosis, necroptosis and pyroptosis in protecting the host against C. rodentium have not been elucidated. Here we used mice with single or combined deficiencies in essential signaling proteins controlling apoptotic, necroptotic or pyroptotic cell death to reveal the roles of these cell death modes in host defense against C. rodentium. Gastrointestinal C. rodentium infections in mice lacking GSDMD and/or MLKL showed that both pyroptosis and necroptosis were dispensable for pathogen clearance. In contrast, while RIPK3-deficient mice showed normal C. rodentium clearance, mice with combined caspase-8 and RIPK3 deficiencies failed to clear intestinal pathogen loads. Although this demonstrated a crucial role for caspase-8 signaling in establishing intestinal host defense, Casp8