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Bacillus anthracis Toxins: Efficient Biochemical Weapons for the Infectious Battle

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Microbial Toxins

Part of the book series: Toxinology ((TOXI))

Abstract

Edema and lethal toxins represent two of the main virulence factors of Bacillus anthracis. They are formed by three components: protective antigen (PA, the binding component), edema factor (EF), and lethal factor (LF) that can associate to give lethal toxin (LT) and edema toxin (ET). EF and LF bear the activity, which are an adenylate cyclase and a metalloprotease, respectively. During the last two decades, numerous studies have improved our knowledge about the biochemical effects of these toxins.

The main biochemical effects of the toxins are presented first, describing how the toxins enter target cells through binding with receptors and are finally delivered to the cytosol. In a second section, the critical targets of the toxins, during the early and late stages of the infection, are discussed.

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References

  • Abrami L, et al. Anthrax toxin triggers endocytosis of its receptor via a lipid raft-mediated clathrin-dependent process. J Cell Biol. 2003;160(3):321–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Abrami L, et al. Membrane insertion of anthrax protective antigen and cytoplasmic delivery of lethal factor occur at different stages of the endocytic pathway. J Cell Biol. 2004;166(5):645–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Abrami L, et al. Functional interactions between anthrax toxin receptors and the WNT signalling protein LRP6. Cell Microbiol. 2008;10(12):2509–19.

    Article  CAS  PubMed  Google Scholar 

  • Abrami L, Kunz B, van der Goot FG. Anthrax toxin triggers the activation of src-like kinases to mediate its own uptake. Proc Natl Acad Sci U S A. 2010a;107(4):1420–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Abrami L, et al. Endocytosis of the anthrax toxin is mediated by clathrin, actin and unconventional adaptors. PLoS Pathog. 2010b;6(3):e1000792.

    Article  PubMed  PubMed Central  Google Scholar 

  • Abrami L, et al. Hijacking multivesicular bodies enables long-term and exosome-mediated long-distance action of anthrax toxin. Cell Rep. 2013;5(4):986–96.

    Article  CAS  PubMed  Google Scholar 

  • Abramova FA, et al. Pathology of inhalational anthrax in 42 cases from the Sverdlovsk outbreak of 1979. Proc Natl Acad Sci U S A. 1993;90(6):2291–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boyden ED, Dietrich WF. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet. 2006;38(2):240–4.

    Article  CAS  PubMed  Google Scholar 

  • Boyer AE, et al. Lethal factor toxemia and anti-protective antigen antibody activity in naturally acquired cutaneous anthrax. J Infect Dis. 2011;204(9):1321–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bradley KA, et al. Identification of the cellular receptor for anthrax toxin. Nature. 2001;414(6860):225–9.

    Article  CAS  PubMed  Google Scholar 

  • Cleret A, et al. Lung dendritic cells rapidly mediate anthrax spore entry through the pulmonary route. J Immunol. 2007;178(12):7994–8001.

    Article  CAS  PubMed  Google Scholar 

  • Cleret-Buhot A, et al. Both lethal and edema toxins of Bacillus anthracis disrupt the human dendritic cell chemokine network. PLoS One. 2012;7(8):e43266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corre JP, et al. In vivo germination of Bacillus anthracis spores during murine cutaneous infection. J Infect Dis. 2013;207(3):450–7.

    Article  CAS  PubMed  Google Scholar 

  • Cote CK, et al. The detection of protective antigen (PA) associated with spores of Bacillus anthracis and the effects of anti-PA antibodies on spore germination and macrophage interactions. Microb Pathog. 2005;38(5–6):209–25.

    Article  CAS  PubMed  Google Scholar 

  • Cui X, et al. Bacillus anthracis edema and lethal toxin have different hemodynamic effects but function together to worsen shock and outcome in a rat model. J Infect Dis. 2007;195(4):572–80.

    Article  CAS  PubMed  Google Scholar 

  • Dumetz F, et al. Noninvasive imaging technologies reveal edema toxin as a key virulence factor in anthrax. Am J Pathol. 2011;178(6):2523–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duong S, Chiaraviglio L, Kirby JE. Histopathology in a murine model of anthrax. Int J Exp Pathol. 2006;87(2):131–7.

    Article  PubMed  PubMed Central  Google Scholar 

  • Feld GK, Brown MJ, Krantz BA. Ratcheting up protein translocation with anthrax toxin. Protein Sci. 2012;21(5):606–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Firoved AM, et al. Bacillus anthracis edema toxin causes extensive tissue lesions and rapid lethality in mice. Am J Pathol. 2005;167(5):1309–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friedlander AM. Macrophages are sensitive to anthrax lethal toxin through an acid-dependent process. J Biol Chem. 1986;261(16):7123–6.

    CAS  PubMed  Google Scholar 

  • Friedlander AM, et al. Characterization of macrophage sensitivity and resistance to anthrax lethal toxin. Infect Immun. 1993;61(1):245–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ghosh CC, et al. Impaired function of the Tie-2 receptor contributes to vascular leakage and lethality in anthrax. Proc Natl Acad Sci U S A. 2012;109(25):10024–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gnade BT, et al. Emergence of anthrax edema toxin as a master manipulator of macrophage and B cell functions. Toxins (Basel). 2010;2(7):1881–97.

    Article  CAS  Google Scholar 

  • Guarner J, et al. Pathology and pathogenesis of bioterrorism-related inhalational anthrax. Am J Pathol. 2003;163(2):701–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guichard A, et al. Anthrax toxins cooperatively inhibit endocytic recycling by the Rab11/Sec15 exocyst. Nature. 2010;467(7317):854–8.

    Article  CAS  PubMed  Google Scholar 

  • Guichard A, Nizet V, Bier E. New insights into the biological effects of anthrax toxins: linking cellular to organismal responses. Microbes Infect. 2012;14(2):97–118.

    Article  CAS  PubMed  Google Scholar 

  • Hicks CW, et al. An overview of anthrax infection including the recently identified form of disease in injection drug users. Intensive Care Med. 2012;38(7):1092–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hong J, et al. Anthrax edema toxin inhibits endothelial cell chemotaxis via Epac and Rap1. J Biol Chem. 2007;282(27):19781–7.

    Article  CAS  PubMed  Google Scholar 

  • Jelacic TM, et al. Exposure to Bacillus anthracis capsule results in suppression of human monocyte-derived dendritic cells. Infect Immun. 2014;82(8):3405–16.

    Article  PubMed  PubMed Central  Google Scholar 

  • Jiang J, et al. Atomic structure of anthrax protective antigen pore elucidates toxin translocation. Nature. 2015;521(7553):545–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kintzer AF, et al. The protective antigen component of anthrax toxin forms functional octameric complexes. J Mol Biol. 2009;392(3):614–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klezovich-Benard M, et al. Mechanisms of NK cell-macrophage Bacillus anthracis crosstalk: a balance between stimulation by spores and differential disruption by toxins. PLoS Pathog. 2012;8(1):e1002481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuo SR, et al. Anthrax toxin-induced shock in rats is associated with pulmonary edema and hemorrhage. Microb Pathog. 2008;44(6):467–72.

    Article  CAS  PubMed  Google Scholar 

  • Lehmann M, et al. Lung epithelial injury by B. anthracis lethal toxin is caused by MKK-dependent loss of cytoskeletal integrity. PLoS One. 2009;4(3):e4755.

    Article  PubMed  PubMed Central  Google Scholar 

  • Leppla SH. Anthrax toxin edema factor: a bacterial adenylate cyclase that increases cyclic AMP concentrations of eukaryotic cells. Proc Natl Acad Sci U S A. 1982;79(10):3162–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S, et al. Capillary morphogenesis protein-2 is the major receptor mediating lethality of anthrax toxin in vivo. Proc Natl Acad Sci U S A. 2009;106(30):12424–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S, et al. Anthrax toxin targeting of myeloid cells through the CMG2 receptor is essential for establishment of Bacillus anthracis infections in mice. Cell Host Microbe. 2010;8(5):455–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S, et al. Key tissue targets responsible for anthrax-toxin-induced lethality. Nature. 2013;501(7465):63–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S, Moayeri M, Leppla SH. Anthrax lethal and edema toxins in anthrax pathogenesis. Trends Microbiol. 2014;22(6):317–25.

    Article  PubMed  PubMed Central  Google Scholar 

  • Maddugoda MP, et al. cAMP signaling by anthrax edema toxin induces transendothelial cell tunnels, which are resealed by MIM via Arp2/3-driven actin polymerization. Cell Host Microbe. 2011;10(5):464–74.

    Article  CAS  PubMed  Google Scholar 

  • Makino S, et al. Effect of the lower molecular capsule released from the cell surface of Bacillus anthracis on the pathogenesis of anthrax. J Infect Dis. 2002;186(2):227–33.

    Article  CAS  PubMed  Google Scholar 

  • Martchenko M, Jeong SY, Cohen SN. Heterodimeric integrin complexes containing beta1-integrin promote internalization and lethality of anthrax toxin. Proc Natl Acad Sci U S A. 2010;107(35):15583–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayer-Scholl A, et al. Human neutrophils kill Bacillus anthracis. PLoS Pathog. 2005;1(3):e23.

    Article  PubMed  PubMed Central  Google Scholar 

  • Miller CJ, Elliott JL, Collier RJ. Anthrax protective antigen: prepore-to-pore conversion. Biochemistry. 1999;38(32):10432–41.

    Article  CAS  PubMed  Google Scholar 

  • Moayeri M, Leppla SH. Cellular and systemic effects of anthrax lethal toxin and edema toxin. Mol Asp Med. 2009;30(6):439–55.

    Article  CAS  Google Scholar 

  • Moayeri M, et al. Bacillus anthracis lethal toxin induces TNF-alpha-independent hypoxia-mediated toxicity in mice. J Clin Invest. 2003;112(5):670–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moayeri M, et al. Endocrine perturbation increases susceptibility of mice to anthrax lethal toxin. Infect Immun. 2005;73(7):4238–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moayeri M, Wiggins JF, Leppla SH. Anthrax protective antigen cleavage and clearance from the blood of mice and rats. Infect Immun. 2007;75(11):5175–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moayeri M, et al. The heart is an early target of anthrax lethal toxin in mice: a protective role for neuronal nitric oxide synthase (nNOS). PLoS Pathog. 2009;5(5):e1000456.

    Article  PubMed  PubMed Central  Google Scholar 

  • Moayeri M, et al. Inflammasome sensor Nlrp1b-dependent resistance to anthrax is mediated by caspase-1, IL-1 signaling and neutrophil recruitment. PLoS Pathog. 2010;6(12):e1001222.

    Article  PubMed  PubMed Central  Google Scholar 

  • Moayeri M, et al. Anthrax pathogenesis. Annu Rev Microbiol. 2015;69:185–208.

    Article  CAS  PubMed  Google Scholar 

  • Mock M, Fouet A. Anthrax. Annu Rev Microbiol. 2001;55:647–71.

    Article  CAS  PubMed  Google Scholar 

  • Ouyang W, et al. Anthrax lethal toxin inhibits translation of hypoxia-inducible factor 1alpha and causes decreased tolerance to hypoxic stress. J Biol Chem. 2014;289(7):4180–90.

    Article  CAS  PubMed  Google Scholar 

  • Park JM, et al. Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science. 2002;297(5589):2048–51.

    Article  CAS  PubMed  Google Scholar 

  • Savransky V, et al. Pathology and pathophysiology of inhalational anthrax in a guinea pig model. Infect Immun. 2013;81(4):1152–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun C, et al. Anthrax lethal toxin disrupts intestinal barrier function and causes systemic infections with enteric bacteria. PLoS One. 2012;7(3):e33583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun DS, et al. Acquired coagulant factor VIII deficiency induced by Bacillus anthracis lethal toxin in mice. Virulence. 2015;6(5):466–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang WJ, Guo Q. The adenylyl cyclase activity of anthrax edema factor. Mol Asp Med. 2009;30(6):423–30.

    Article  CAS  Google Scholar 

  • Terra JK, et al. Cutting edge: resistance to Bacillus anthracis infection mediated by a lethal toxin sensitive allele of Nalp1b/Nlrp1b. J Immunol. 2010;184(1):17–20.

    Article  CAS  PubMed  Google Scholar 

  • Tonello F, Montecucco C. The anthrax lethal factor and its MAPK kinase-specific metalloprotease activity. Mol Asp Med. 2009;30(6):431–8.

    Article  CAS  Google Scholar 

  • Tournier JN, et al. Anthrax toxins: a weapon to systematically dismantle the host immune defenses. Mol Asp Med. 2009;30(6):456–66.

    Article  CAS  Google Scholar 

  • Trescos Y, et al. Micropatterned macrophage analysis reveals global cytoskeleton constraints induced by Bacillus anthracis edema toxin. Infect Immun. 2015;83(8):3114–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vasconcelos D, et al. Pathology of inhalation anthrax in cynomolgus monkeys (Macaca fascicularis). Lab Investig. 2003;83(8):1201–9.

    Article  PubMed  Google Scholar 

  • Vitale G, et al. Anthrax lethal factor cleaves the N-terminus of MAPKKs and induces tyrosine/threonine phosphorylation of MAPKs in cultured macrophages. Biochem Biophys Res Commun. 1998;248(3):706–11.

    Article  CAS  PubMed  Google Scholar 

  • Warfel JM, Steele AD, D’Agnillo F. Anthrax lethal toxin induces endothelial barrier dysfunction. Am J Pathol. 2005;166(6):1871–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei W, et al. The LDL receptor-related protein LRP6 mediates internalization and lethality of anthrax toxin. Cell. 2006;124(6):1141–54.

    Article  CAS  PubMed  Google Scholar 

  • Welkos SL, Friedlander AM. Pathogenesis and genetic control of resistance to the Sterne strain of Bacillus anthracis. Microb Pathog. 1988;4(1):53–69.

    Article  CAS  PubMed  Google Scholar 

  • Young JA, Collier RJ. Anthrax toxin: receptor binding, internalization, pore formation, and translocation. Annu Rev Biochem. 2007;76:243–65.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Unité Interactions Hôte-agents pathogènes, Institut de recherche biomédicale des armées (IRBA), Brétigny-sur-Orge, France

    Yannick Trescos, Clémence Rougeaux & Jean-Nicolas Tournier

  2. Ecole du Val-de-Grâce, Paris, France

    Yannick Trescos & Jean-Nicolas Tournier

  3. Laboratoire Pathogénie des Toxi-Infections Bactériennes, Institut Pasteur, Paris, France

    Yannick Trescos, Clémence Rougeaux & Jean-Nicolas Tournier

  4. National Reference Center for Anthrax, IRBA, Brétigny-sur-Orge, France

    Jean-Nicolas Tournier

Authors
  1. Yannick Trescos
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  2. Clémence Rougeaux
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  3. Jean-Nicolas Tournier
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Corresponding author

Correspondence to Yannick Trescos .

Editor information

Editors and Affiliations

  1. Biology Department, Wilson College, Chambersburg, Pennsylvania, USA

    Brad Stiles

  2. Department of Biochemistry, School of Medicine and Instituto Clodomiro Picado, Faculty of Microbiology, University of Costa Rica, San Pedro de Montes de Oca, Costa Rica

    Alberto Alape-Girón

  3. Department of Pathology and Microbiology, Université de Montréal, Saint-Hyacinthe, Québec, Canada

    J. Daniel Dubreuil

  4. College of Pharmacy, Roseman University of Health Sciences, Henderson, Nevada, USA

    Manas Mandal

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Trescos, Y., Rougeaux, C., Tournier, JN. (2018). Bacillus anthracis Toxins: Efficient Biochemical Weapons for the Infectious Battle. In: Stiles, B., Alape-Girón, A., Dubreuil, J., Mandal, M. (eds) Microbial Toxins. Toxinology. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6449-1_8

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