Bacillus anthracis induces NLRP3 inflammasome activation and caspase-8–mediated apoptosis of macrophages to promote lethal anthrax

Abstract

Significance Anthrax is a deadly infection caused by exposure to Bacillus anthracis bacteria. Anthrax lethal toxin (LeTx) has long been recognized as a major determinant of lethal anthrax, which paralyzes the host’s immune defenses by killing off macrophages. Despite the importance of macrophage cytotoxicity in anthrax pathogenesis, the signaling pathways underlying cell death of B. anthracis -infected macrophages are poorly understood. This study shows that infection with live B. anthracis or LeTx intoxication sensitizes macrophages to TNF-dependent NLRP3 inflammasome activation and caspase-8–mediated apoptosis. Moreover, caspase-8–mediated apoptosis is shown to promote anthrax-associated lethality in vivo. Collectively, the study establishes TNF- and RIPK1 kinase activity–dependent NLRP3 inflammasome activation and macrophage apoptosis as key host–pathogen mechanisms in lethal anthrax.