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Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin

Abstract

Anthrax poses a clear and present danger as an agent of biological terrorism1,2,3. Infection with Bacillus anthracis, the causative agent of anthrax, if untreated can result in rampant bacteraemia, multisystem dysfunction and death4,5,6,7,8. Anthrax lethal toxin (LT) is a critical virulence factor of B. anthracis, which occurs as a complex of protective antigen and lethal factor. Here we demonstrate that LT severely impairs the function of dendritic cells—which are pivotal to the establishment of immunity against pathogens—and host immune responses by disrupting the mitogen-activated protein (MAP) kinase intracellular signalling network. Dendritic cells exposed to LT and then stimulated with lipopolysaccharide do not upregulate co-stimulatory molecules, secrete greatly diminished amounts of proinflammatory cytokines, and do not effectively stimulate antigen-specific T cells in vivo. Furthermore, injections of LT induce a profound impairment of antigen-specific T- and B-cell immunity. These data suggest a role for LT in suppressing host immunity during B. anthracis infections, and represent an immune evasion strategy, where a microbe targets MAP kinases in dendritic cells to disarm the immune response.

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Figure 1: LT impairs dendritic cell function in vitro.
Figure 2: LT-treated dendritic cells impair T-cell responses in vivo.
Figure 3: LT impairs antigen-specific T- and B-cell responses in vivo.
Figure 4: LT impairs phosphorylation of p38 and ERK1/2 in dendritic cells.

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Acknowledgements

We thank R. Ahmed and S. Mahanty for critical review of this manuscript. This work was supported by grants from the NIH and CDC.

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Correspondence to Bali Pulendran.

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Agrawal, A., Lingappa, J., Leppla, S. et al. Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin. Nature 424, 329–334 (2003). https://doi.org/10.1038/nature01794

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