Anthrax Lethal Toxin-Mediated Killing of Human and Murine Dendritic Cells Impairs the Adaptive Immune Response

Abstract

Many pathogens have acquired strategies to combat the immune response. Bacillus anthracis interferes with host defenses by releasing anthrax lethal toxin (LT), which inactivates mitogen-activated protein kinase pathways, rendering dendritic cells (DCs) and T lymphocytes nonresponsive to immune stimulation. However, these cell types are considered resistant to killing by LT. Here we show that LT kills primary human DCs in vitro, and murine DCs in vitro and in vivo. Kinetics of LT-mediated killing of murine DCs, as well as cell death pathways induced, were dependent upon genetic background: LT triggered rapid necrosis in BALB/c-derived DCs, and slow apoptosis in C57BL/6-derived DCs. This is consistent with rapid and slow killing of LT-injected BALB/c and C57BL/6 mice, respectively. We present evidence that anthrax LT impairs adaptive immunity by specifically targeting DCs. This may represent an immune-evasion strategy of the bacterium, and contribute to anthrax disease progression. We also established that genetic background determines whether apoptosis or necrosis is induced by LT. Finally, killing of C57BL/6-derived DCs by LT mirrors that of human DCs, suggesting that C57BL/6 DCs represent a better model system for human anthrax than the prototypical BALB/c macrophages. Dendritic cells (DCs) are specialized white blood cells that identify and present antigens to immune cells, T cells, in order to mount an immune response targeted against specific pathogens. DCs are critical to a host's defense against infection. Previous work has shown that the anthrax bacterium disables many immune cells, including DCs, through the action of a released toxin, lethal toxin. Here the authors show that lethal toxin efficiently kills both human and murine DCs. The means by which DCs were killed by the anthrax toxin were notably distinct and dependent on their genetic background. Human DCs, as well as those derived from the murine strain C57BL/6, died over the course of 72 h via activation of apoptosis, or programmed cell death. DCs from BALB/c mice, however, died rapidly of a necrotic cell death following toxin exposure. As human and C57BL/6 DCs share an identical response to anthrax toxin, C57BL/6 mice appear to provide an excellent model for human anthrax. The study's findings suggest that specific targeting of DCs by the anthrax toxin impairs the immune response of the infected host, and the authors believe that this strategy promotes spread of the bacterium and disease progression.