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

Abstract

AbstractYersiniaare gram-negative zoonotic bacteria that use a type III secretion system (T3SS) to injectYersiniaouter proteins (Yops) into the host cytosol to subvert essential components of innate immune signaling. However,Yersiniavirulence activities can elicit activation of inflammasomes, which lead to inflammatory cell death and cytokine release to contain infection.Yersiniaactivation 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 intestinalYersiniainfection. In contrast to murine macrophages, we find that in both human IECs and macrophages,Yersinia pseudotuberculosisT3SS 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 inhibitingYersiniainternalization mediated by YadA and β1-integrin signaling. These data provide insight into the mechanisms ofYersinia-mediated inflammasome activation and evasion in human cells, and reveal species-specific differences underlying regulation of inflammasome responses toYersinia.ImportanceYersiniaare responsible for significant disease burdens in humans, ranging from recurrent disease outbreaks (yersiniosis) to pandemics (Yersinia pestisplague). Together with rising antibiotic resistance rates, there is a critical need to better understandYersiniapathogenesis and host immune mechanisms, as this information will aid in developing improved immunomodulatory therapeutics. Inflammasome responses in human cells are less studied relative to murine models of infection, though recent studies have uncovered key differences in inflammasome responses between mice and humans. Here, we dissect human intestinal epithelial cell and macrophage inflammasome responses toYersinia pseudotuberculosis.Our findings provide insight into species- and cell type-specific differences in inflammasome responses toYersinia.