Yersinia Type III-Secreted Effectors Evade the Caspase-4 Inflammasome in Human Cells

Yersinia are gram-negative zoonotic bacteria that use a type III secretion system (T3SS) to inject Yersinia outer proteins (Yops) into the host cytosol to subvert essential components of innate immune signaling. However, Yersinia virulence activities can elicit activation of inflammasomes, which lead to inflammatory cell death and cytokine release to contain infection. Yersinia activation and evasion of inflammasomes have been characterized in murine macrophages but remain poorly defined in human cells, particularly intestinal epithelial cells (IECs), a primary site of intestinal Yersinia infection. In contrast to murine macrophages, we find that in both human IECs and macrophages, Yersinia pseudotuberculosis T3SS effectors enable evasion of the caspase-4 inflammasome, which senses cytosolic lipopolysaccharide (LPS). The antiphagocytic YopE and YopH, as well as the translocation regulator YopK, were collectively responsible for evading inflammasome activation, in part by inhibiting Yersinia internalization mediated by YadA and β1-integrin signaling. These data provide insight into the mechanisms of Yersinia-mediated inflammasome activation and evasion in human cells, and reveal species-specific differences underlying regulation of inflammasome responses to Yersinia.