Activation of inflammasome by rickettsiae in human and murine macrophages (MPF4P.727)

Abstract

Abstract Rickettsiae are Gram-negative, obligately intracellular bacteria that infect macrophages. However, the molecular mechanisms involved in interaction of rickettsiae with macrophages remain poorly understood. In this study, we investigated the inflammasome activation by rickettsiae in human and mouse macrophages. R. australis activated the inflammasome in mouse bone-marrow derived macrophages (BMDM), marked by caspase (casp)-1/11-dependent secretion of IL-1β and IL-18, and induction of pyroptosis. Kinetic studies revealed that low dose (MOI 2) R. australis activated the inflammasome in mouse macrophages at 12 h post infection (p.i.), while high dose (MOI 6) activated at 8 h p.i., with no significant difference in activation between doses at 24 h p.i.. In contrast, R. australis activated the inflammasome in human THP-1 derived macrophages at as early as 3 h p.i., resulting in production of IL-1β, IL-18, induction of pyroptosis, and activation of casp-1. Studies using siRNA and inhibitors specific for casp-4 suggest that rickettsiae activated non-canonical inflammasome pathway in human macrophages. Taken together, our data, for the first time, illustrated the activation of inflammasome by rickettsiae in both mouse and human macrophages, although with different kinetic mechanisms. This study provides invaluable information for developing novel therapeutic interventions for rickettsioses by employing current knowledge derived from mouse infection models.