Mechanisms of Non-canonical Inflammasome Activation by Rickettsia

Abstract

Abstract Rickettsiae are Gram-negative, obligately intracellular bacteria that infect macrophages, however, the molecular mechanisms involved in the interactions of rickettsiae with macrophages remain poorly understood. We have found that R. australis activates the inflammasome in mouse primary macrophages as evidenced by caspase-1/11-dependent secretion of IL-1β as well as the cleavage of caspase-1 in both cell lysates and supernatant. In the present study, we show the cleavage of caspase-11 and the induction of pyroptosis in mouse macrophages upon infection with R. australis. Furthermore, inhibitors of caspase-4 significantly reduced the levels of IL-1β secreted by infected human macrophages. Our results suggest that rickettsiae also activate caspase-11/4-dependent noncanonical inflammasome in macrophages. We are currently investigating the role of cytosolic rickettsial lipopolysaccharide (LPS) in activating noncanonical inflammasome in mouse and human macrophages and the molecular mechanisms involved. Considering the distinct features of rickettsial LPS from other obligately intracellular Gram-negative bacteria, our studies will not only provide novel activating mechanisms of noncanonical inflammasome by employing rickettsiae as an infection model, but also help us to better understand the immune pathogenesis of fatal rickettsioses.