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Published on: August 1, 2013
Anthrax lethal toxin-mediated killing of human and murine dendritic cells impairs the adaptive immune response
Abdelkrim Alileche1, Evan R Serfass, Stefan M Muehlbauer
1Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
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.
Insights
Anthrax lethal toxin (LT) kills dendritic cells (DCs), impairing adaptive immunity. This killing mechanism, whether necrosis or apoptosis, depends on host genetics, with C57BL/6 DCs serving as a better human anthrax model.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Pathogens like Bacillus anthracis evade immune responses.
- Anthrax lethal toxin (LT) disrupts immune signaling pathways.
- Dendritic cells (DCs) and T lymphocytes are key immune cells targeted by LT.
Purpose of the Study:
- To investigate the killing of dendritic cells (DCs) by anthrax lethal toxin (LT).
- To determine the mechanisms and genetic dependencies of LT-induced cell death in DCs.
- To evaluate the suitability of murine DC models for studying human anthrax.
Main Methods:
- In vitro and in vivo experiments using primary human and murine DCs.
- Analysis of LT-mediated cell death pathways (apoptosis and necrosis).
- Comparison of LT effects on DCs from different mouse genetic backgrounds (BALB/c and C57BL/6).
Main Results:
- LT effectively kills human and murine DCs, contradicting previous assumptions of resistance.
- LT induces rapid necrosis in BALB/c DCs and slow apoptosis in C57BL/6 DCs.
- LT-induced DC killing impairs adaptive immunity, suggesting an immune evasion strategy.
Conclusions:
- Anthrax LT directly kills DCs, impacting adaptive immunity and disease progression.
- Host genetic background dictates the mode of LT-induced DC death (necrosis vs. apoptosis).
- C57BL/6 DCs are a more relevant model for human anthrax than BALB/c macrophages due to similar LT-induced cell death kinetics.
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