Extracellular mycobacterial DNA drives disease progression by triggering Caspase-11-dependent pyroptosis of infected macrophages

Abstract

Deregulated inflammation seriously complicates life-threatening microbial infections, including tuberculosis (TB). Assembly of multiprotein inflammasome complexes is an important trigger of inflammation, but how this impacts TB progression remains unknown. Here, in vivo imaging in the zebrafish TB model revealed that mycobacterial expansion in TB granulomas is driven by inflammasomes and ensuing pyroptotic cell death of infected macrophages. We show that an Asc-independent pathway induces macrophage pyroptosis and impairs host resistance, in contrast to host-protective roles of Asc-dependent inflammasome activation and Il1b secretion. Using ASC-deficient murine macrophages, we demonstrate extracellular bacterial DNA to induce CASP11-dependent pyroptosis in a manner dependent on phagosome permeabilization. Finally, we propose that mycobacteria induce pyroptosis to escape cell-in-cell structures, formed within granulomas when living infected cells are engulfed by neighbor cells. This study provides new insight into the role of pyroptosis in TB pathogenesis and reveals a novel link between nucleic acid sensing and CASP11-dependent pyroptosis.