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.
Highlights
Bacillus anthracis, the causative agent of anthrax disease [1], releases lethal toxin (LT), which is sufficient to cause death in mice even in the absence of the bacterium [2]
To determine whether the impairment of DCs could be due to cytopathic effects mediated by LT, we generated immature monocyte-derived dendritic cells (MoDCs) from human peripheral blood monocytes
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
Summary
The causative agent of anthrax disease [1], releases lethal toxin (LT), which is sufficient to cause death in mice even in the absence of the bacterium [2]. Broad cytopathic and lethal effects associated with B. anthracis infection can be reproduced by LT injection of mice [3,4]. PA binds to specific cell surface receptors and mediates endocytosis of LF, a metalloprotease [5,6]. Despite ubiquitous uptake by mammalian cells, LT kills only a few cell types, including murine macrophages [3,4]. Susceptibility of murine macrophages to LT killing is strain-specific, and is controlled by a region of Chromosome 11 that encodes the kinesin-like motor protein Kif1c [9,10]
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