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Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin

Nature volume 424, pages 329–334 (2003)Cite this article

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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References

  1. Mourez, M. et al. 2001: a year of major advances in anthrax toxin research. Trends Microbiol. 10, 287–293 (2002)

    Article  CAS  PubMed  Google Scholar 

  2. Dixon, T. C., Meselson, M., Guillemin, J. & Hanna, P. C. Anthrax. N. Engl. J. Med. 341, 815–826 (1999)

    Article  CAS  PubMed  Google Scholar 

  3. Lane, H. C., Montagne, J. L. & Fauci, A. Bioterrorism: a clear and present danger. Nature Med. 7, 1271–1273 (2001)

    Article  CAS  PubMed  Google Scholar 

  4. Mock, M. & Fouet, A. Anthrax. Annu. Rev. Microbiol. 55, 647–671 (2001)

    Article  CAS  PubMed  Google Scholar 

  5. Little, S. F. & Ivins, B. E. Molecular pathogenesis of Bacillus anthracis infection. Microbes Infect. 1, 131–139 (1999)

    Article  CAS  PubMed  Google Scholar 

  6. Hanna, P. C. & Ireland, J. A. Understanding Bacillus anthracis pathogenesis. Trends Microbiol. 7, 180–182 (1999)

    Article  CAS  PubMed  Google Scholar 

  7. Smith, H. Discovery of the anthrax toxin: the beginning of in vivo studies on pathogenic bacteria. Trends Microbiol. 8, 199–200 (2000)

    Article  CAS  PubMed  Google Scholar 

  8. Brossier, F. & Mock, M. Toxins of Bacillus anthracis. Toxicon 39, 1747–1755 (2001)

    Article  CAS  PubMed  Google Scholar 

  9. Bradley, K. A., Mogridge, J., Mourez, M., Collier, R. J. & Young, J. A. Identification of the cellular receptor for anthrax toxin. Nature 414, 225–229 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Duesbery, N. S. et al. Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science 280, 734–737 (1998)

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Vitale, G., Bernardi, L., Napolitani, G., Mock, M. & Montecucco, C. Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochem. J. 352, 739–745 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pellizzari, R., Guidi-Rontani, C., Vitale, G., Mock, M. & Montecucco, C. Anthrax lethal factor cleaves MKK3 in macrophages and inhibits the LPS/IFNγ-induced release of NO and TNFα. FEBS Lett. 462, 199–204 (1999)

    Article  CAS  PubMed  Google Scholar 

  13. Park, J. M., Greten, F. R., Li, Z. W. & Karin, M. Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science 297, 2048–2051 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  14. Dong, C., Davis, R. J. & Flavell, R. A. MAP Kinases in the immune response. Annu. Rev. Immunol. 20, 55–72 (2002)

    Article  CAS  PubMed  Google Scholar 

  15. Hanna, P. C., Acosta, D. & Collier, R. J. On the role of macrophages in anthrax. Proc. Natl Acad. Sci. USA 90, 10198–10201 (1993)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. Banchereau, J. & Steinman, R. M. Dendritic cells. Nature 392, 245–252 (1998)

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Pulendran, B., Palucka, K. & Banchereau, J. Sensing pathogens and tuning immune responses. Science 293, 253–256 (2001)

    Article  CAS  PubMed  Google Scholar 

  18. Liu, Y.-J. Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell 106, 259–262 (2001)

    Article  CAS  PubMed  Google Scholar 

  19. Shortman, K. & Liu, Y-J. Mouse and human dendritic cell subtypes. Nature Rev. Immunol. 2, 151–161 (2002)

    Article  CAS  Google Scholar 

  20. Jernigan, D. B. et al. Investigation of bioterrorism-related anthrax, United States, 2001: epidemiologic findings. Emerg. Infect. Dis. 8, 1019–1028 (2002)

    Article  PubMed  PubMed Central  Google Scholar 

  21. Pulendran, B. et al. Developmental pathways of dendritic cells in vivo: distinct function, phenotype, and localization of dendritic cell subsets in FLT3 ligand-treated mice. J. Immunol. 159, 2222–2231 (1997)

    CAS  PubMed  Google Scholar 

  22. Sailaja, G. et al. Long-term maintenance of gp120-specific immune responses by genetic vaccination with the HIV-1 envelope genes linked to the gene encoding Flt-3 ligand. J. Immunol. 170, 2496–2507 (2003)

    Article  CAS  PubMed  Google Scholar 

  23. Liu, L. et al. Visualization and quantification of T cell-mediated cytotoxicity using cell-permeable fluorogenic caspase substrates. Nature Med. 8, 185–189 (2002)

    Article  CAS  PubMed  Google Scholar 

  24. Kearney, E. R., Pape, K. A., Loh, D. Y. & Jenkins, M. K. Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1, 327–339 (1994)

    Article  CAS  PubMed  Google Scholar 

  25. Haskins, K. et al. The major histocompatibility complex-restricted antigen receptor on T cells. I. Isolation with a monoclonal antibody. J. Exp. Med. 157, 1149–1169 (1983)

    Article  CAS  PubMed  Google Scholar 

  26. Ingulli, E., Mondino, A., Khoruts, A. & Jenkins, M. K. In vivo detection of dendritic cell antigen presentation to CD4(+ ) T cells. J. Exp. Med. 185, 2133–2144 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yi, A. K. et al. Role of mitogen-activated protein kinases in CpG DNA-mediated IL-10 and IL-12 production: central role of extracellular signal-regulated kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. J. Immunol. 168, 4711–4720 (2002)

    Article  CAS  PubMed  Google Scholar 

  28. Yi, A. K. et al. Lipopolysaccharide and CpG DNA synergize for tumor necrosis factor-α production through activation of NF-kB. Int. Immunol. 13, 1391–1404 (2002)

    Article  Google Scholar 

  29. Pannifer, A. D. et al. Crystal structure of the anthrax lethal factor. Nature 414, 229–233 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  30. Petosa, C. et al. Crystal structure of the anthrax protective antigen. Nature 385, 833–838 (1997)

    Article  ADS  CAS  PubMed  Google Scholar 

Download references

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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Authors and Affiliations

  1. Emory Vaccine Research Center, 954 Gatewood Road, Atlanta, Georgia, 30329, USA

    Anshu Agrawal, Sudhanshu Agrawal, Abdul Jabbar & Bali Pulendran

  2. Meningitis and Special Pathogens Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, 30333, Georgia, USA

    Jai Lingappa & Conrad Quinn

  3. Microbial Pathogenesis Section, NIAID, Bethesda, Maryland, 20892-4350, USA

    Stephen H. Leppla

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  1. Anshu Agrawal
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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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