1932

Abstract

Anthrax is caused by the spore-forming, gram-positive bacterium . The bacterium's major virulence factors are () the anthrax toxins and () an antiphagocytic polyglutamic capsule. These are encoded by two large plasmids, the former by pXO1 and the latter by pXO2. The expression of both is controlled by the bicarbonate-responsive transcriptional regulator, AtxA. The anthrax toxins are three polypeptides—protective antigen (PA), lethal factor (LF), and edema factor (EF)—that come together in binary combinations to form lethal toxin and edema toxin. PA binds to cellular receptors to translocate LF (a protease) and EF (an adenylate cyclase) into cells. The toxins alter cell signaling pathways in the host to interfere with innate immune responses in early stages of infection and to induce vascular collapse at late stages. This review focuses on the role of anthrax toxins in pathogenesis. Other virulence determinants, as well as vaccines and therapeutics, are briefly discussed.

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2015-10-15
2024-04-18
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Literature Cited

  1. Abrami L, Bischofberger M, Kunz B, Groux R, van der Goot FG. 1.  2010. Endocytosis of the anthrax toxin is mediated by clathrin, actin and unconventional adaptors. PLOS Pathog. 6:e1000792 [Google Scholar]
  2. Abrami L, Brandi L, Moayeri M, Brown MJ, Krantz BA. 2.  et al. 2013. Hijacking multivesicular bodies enables long-term and exosome-mediated long-distance action of anthrax toxin. Cell Rep. 5:986–96 [Google Scholar]
  3. Abrami L, Kunz B, van der Goot FG. 3.  2010. Anthrax toxin triggers the activation of src-like kinases to mediate its own uptake. PNAS 107:1420–24 [Google Scholar]
  4. Abrami L, Leppla SH, van der Goot FG. 4.  2006. Receptor palmitoylation and ubiquitination regulate anthrax toxin endocytosis. J. Cell Biol. 172:309–20 [Google Scholar]
  5. Abrami L, Lindsay M, Parton RG, Leppla SH, van der Goot FG. 5.  2004. Membrane insertion of anthrax protective antigen and cytoplasmic delivery of lethal factor occur at different stages of the endocytic pathway. J. Cell Biol. 166:645–51 [Google Scholar]
  6. Abrami L, Liu S, Cosson P, Leppla SH, van der Goot FG. 6.  2003. Anthrax toxin triggers endocytosis of its receptor via a lipid raft-mediated clathrin-dependent process. J. Cell Biol. 160:321–28 [Google Scholar]
  7. Agaisse H, Gominet M, Okstad OA, Kolsto AB, Lereclus D. 7.  1999. PlcR is a pleiotropic regulator of extracellular virulence factor gene expression in Bacillus thuringiensis. Mol. Microbiol. 32:1043–53 [Google Scholar]
  8. Agrawal A, Lingappa J, Leppla SH, Agrawal S, Jabbar A. 8.  et al. 2003. Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin. Nature 424:329–34 [Google Scholar]
  9. Alileche A, Serfass ER, Muehlbauer SM, Porcelli SA, Brojatsch J. 9.  2005. Anthrax lethal toxin-mediated killing of human and murine dendritic cells impairs the adaptive immune response. PLOS Pathog. 1:e19 [Google Scholar]
  10. Arora N, Leppla SH. 10.  1993. Residues 1–254 of anthrax toxin lethal factor are sufficient to cause cellular uptake of fused polypeptides. J. Biol. Chem. 268:3334–41 [Google Scholar]
  11. Aulinger BA, Roehrl MH, Mekalanos JJ, Collier RJ, Wang JY. 11.  2005. Combining anthrax vaccine and therapy: A dominant-negative inhibitor of anthrax toxin is also a potent and safe immunogen for vaccines. Infect. Immun. 73:3408–14 [Google Scholar]
  12. Barson HV, Mollenkopf H, Kaufmann SH, Rijpkema S. 12.  2008. Anthrax lethal toxin suppresses chemokine production in human neutrophil NB-4 cells. Biochem. Biophys. Res. Commun. 374:288–93 [Google Scholar]
  13. Bartkus JM, Leppla SH. 13.  1989. Transcriptional regulation of the protective antigen gene of Bacillus anthracis. Infect. Immun. 57:2295–300 [Google Scholar]
  14. Basha S, Rai P, Poon V, Saraph A, Gujraty K. 14.  et al. 2006. Polyvalent inhibitors of anthrax toxin that target host receptors. PNAS 103:13509–13 [Google Scholar]
  15. Batty S, Chow EM, Kassam A, Der SD, Mogridge J. 15.  2006. Inhibition of mitogen-activated protein kinase signalling by Bacillus anthracis lethal toxin causes destabilization of interleukin-8 mRNA. Cell. Microbiol. 8:130–38 [Google Scholar]
  16. Beall FA, Dalldorf FG. 16.  1966. The pathogenesis of the lethal effect of anthrax toxin in the rat. J. Infect. Dis. 116:377–89 [Google Scholar]
  17. Bellanti JA, Lin FY, Chu C, Shiloach J, Leppla SH. 17.  et al. 2011. Phase 1 study of a recombinant mutant protective antigen of Bacillus anthracis. Clin. Vaccine Immunol. 19:140–45 [Google Scholar]
  18. Bishop BL, Lodolce JP, Kolodziej L, Boone DL, Tang WJ. 18.  2010. The role of anthrolysin O in gut epithelial barrier disruption during Bacillus anthracis infection. Biochem. Biophys. Res. Commun. 394:254–59 [Google Scholar]
  19. Bolcome RE III, Sullivan SE, Zeller R, Barker AP, Collier RJ, Chan J. 19.  2008. Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature. PNAS 105:2439–44 [Google Scholar]
  20. Boyden ED, Dietrich WF. 20.  2006. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat. Genet. 38:240–44 [Google Scholar]
  21. Boyer AE, Quinn CP, Hoffmaster AR, Kozel TR, Saile E. 21.  et al. 2009. Kinetics of lethal factor and poly-d-glutamic acid antigenemia during inhalation anthrax in rhesus macaques. Infect. Immun. 77:3432–41 [Google Scholar]
  22. Bradley KA, Mogridge J, Mourez M, Collier RJ, Young JA. 22.  2001. Identification of the cellular receptor for anthrax toxin. Nature 414:225–29 [Google Scholar]
  23. Bradley KA, Mogridge J, Rainey GJ, Batty S, Young JA. 23.  2003. Binding of anthrax toxin to its receptor is similar to alpha integrin-ligand interactions. J. Biol. Chem. 278:49342–47 [Google Scholar]
  24. Brittingham KC, Ruthel G, Panchal RG, Fuller CL, Ribot WJ. 24.  et al. 2005. Dendritic cells endocytose Bacillus anthracis spores: implications for anthrax pathogenesis. J. Immunol. 174:5545–52 [Google Scholar]
  25. Campbell JD, Clement KH, Wasserman SS, Donegan S, Chrisley L, Kotloff KL. 25.  2007. Safety, reactogenicity and immunogenicity of a recombinant protective antigen anthrax vaccine given to healthy adults. Hum. Vaccin. 3:205–11 [Google Scholar]
  26. Candela T, Dumetz F, Tosi-Couture E, Mock M, Goossens PL, Fouet A. 26.  2012. Cell-wall preparation containing poly-gamma-d-glutamate covalently linked to peptidoglycan, a straightforward extractable molecule, protects mice against experimental anthrax infection. Vaccine 31:171–75 [Google Scholar]
  27. Candela T, Mock M, Fouet A. 27.  2005. CapE, a 47-amino-acid peptide, is necessary for Bacillus anthracis polyglutamate capsule synthesis. J. Bacteriol. 187:7765–72 [Google Scholar]
  28. Cao S, Guo A, Liu Z, Tan Y, Wu G. 28.  et al. 2009. Investigation of new dominant-negative inhibitors of anthrax protective antigen mutants for use in therapy and vaccination. Infect. Immun. 77:4679–87 [Google Scholar]
  29. Cendrowski S, MacArthur W, Hanna P. 29.  2004. Bacillus anthracis requires siderophore biosynthesis for growth in macrophages and mouse virulence. Mol. Microbiol. 51:407–17 [Google Scholar]
  30. Chabot DJ, Joyce J, Caulfield M, Cook J, Hepler R. 30.  et al. 2012. Efficacy of a capsule conjugate vaccine against inhalational anthrax in rabbits and monkeys. Vaccine 30:846–52 [Google Scholar]
  31. Chabot DJ, Scorpio A, Tobery SA, Little SF, Norris SL, Friedlander AM. 31.  2004. Anthrax capsule vaccine protects against experimental infection. Vaccine 23:43–47 [Google Scholar]
  32. Chang HH, Wang TP, Chen PK, Lin YY, Liao CH. 32.  et al. 2013. Erythropoiesis suppression is associated with anthrax lethal toxin-mediated pathogenic progression. PLOS ONE 8:e71718 [Google Scholar]
  33. Chateau A, van Schaik W, Six A, Aucher W, Fouet A. 33.  2011. CodY regulation is required for full virulence and heme iron acquisition in Bacillus anthracis. FASEB J. 25:4445–56 [Google Scholar]
  34. Chavarria-Smith J, Vance RE. 34.  2013. Direct proteolytic cleavage of NLRP1B is necessary and sufficient for inflammasome activation by anthrax lethal factor. PLOS Pathog. 9:e1003452 [Google Scholar]
  35. Chen D, Misra M, Sower L, Peterson JW, Kellogg GE, Schein CH. 35.  2008. Novel inhibitors of anthrax edema factor. Bioorg. Med. Chem. 16:7225–33 [Google Scholar]
  36. Chen PK, Chang HH, Lin GL, Wang TP, Lai YL. 36.  et al. 2013. Suppressive effects of anthrax lethal toxin on megakaryopoiesis. PLOS ONE 8:e59512 [Google Scholar]
  37. Chen Z, Moayeri M, Purcell R. 37.  2011. Monoclonal antibody therapies against anthrax. Toxins 3:1004–19 [Google Scholar]
  38. Chen Z, Schneerson R, Lovchik J, Lyons CR, Zhao H. 38.  et al. 2010. Pre- and postexposure protection against virulent anthrax infection in mice by humanized monoclonal antibodies to Bacillus anthracis capsule. PNAS 108:739–44 [Google Scholar]
  39. Chiang C, Bongiorni C, Perego M. 39.  2011. Glucose-dependent activation of Bacillus anthracis toxin gene expression and virulence requires the carbon catabolite protein CcpA. J. Bacteriol. 193:52–62 [Google Scholar]
  40. Chitlaru T, Altboum Z, Reuveny S, Shafferman A. 40.  2011. Progress and novel strategies in vaccine development and treatment of anthrax. Immunol. Rev. 239:221–36 [Google Scholar]
  41. Chitlaru T, Shafferman A. 41.  2009. Proteomic studies of Bacillus anthracis. Future Microbiol. 4:983–98 [Google Scholar]
  42. Chitlaru T, Zaide G, Ehrlich S, Inbar I, Cohen O, Shafferman A. 42.  2011. HtrA is a major virulence determinant of Bacillus anthracis. Mol. Microbiol. 81:1542–59 [Google Scholar]
  43. Chung MC, Popova TG, Jorgensen SC, Dong L, Chandhoke V. 43.  et al. 2008. Degradation of circulating von Willebrand factor and its regulator ADAMTS13 implicates secreted Bacillus anthracis metalloproteases in anthrax consumptive coagulopathy. J. Biol. Chem. 283:9531–42 [Google Scholar]
  44. Cleret A, Quesnel-Hellmann A, Mathieu J, Vidal D, Tournier JN. 44.  2006. Resident CD11c+ lung cells are impaired by anthrax toxins after spore infection. J. Infect. Dis. 194:86–94 [Google Scholar]
  45. Cleret-Buhot A, Mathieu J, Tournier JN, Quesnel-Hellmann A. 45.  2012. Both lethal and edema toxins of Bacillus anthracis disrupt the human dendritic cell chemokine network. PLOS ONE 7:e43266 [Google Scholar]
  46. Coggeshall KM, Lupu F, Ballard J, Metcalf JP, James JA. 46.  et al. 2013. The sepsis model: an emerging hypothesis for the lethality of inhalation anthrax. J. Cell Mol. Med. 17:914–20 [Google Scholar]
  47. Collier RJ. 47.  2009. Membrane translocation by anthrax toxin. Mol. Aspects Med. 30:413–22 [Google Scholar]
  48. Corre JP, Piris-Gimenez A, Moya-Nilges M, Jouvion G, Glomski IJ. 48.  et al. 2012. In vivo germination of Bacillus anthracis spores during murine cutaneous infection. J. Infect. Dis. 207:450–57 [Google Scholar]
  49. Crawford MA, Aylott CV, Bourdeau RW, Bokoch GM. 49.  2006. Bacillus anthracis toxins inhibit human neutrophil NADPH oxidase activity. J. Immunol. 176:7557–65 [Google Scholar]
  50. Cryan LM, Habeshian KA, Caldwell TP, Morris MT, Ackroyd PC. 50.  et al. 2013. Identification of small molecules that inhibit the interaction of TEM8 with anthrax protective antigen using a FRET assay. J. Biomol. Screen. 18:714–25 [Google Scholar]
  51. Cui X, Li Y, Li X, Haley M, Moayeri M. 51.  et al. 2006. Sublethal doses of Bacillus anthracis lethal toxin inhibit inflammation with lipopolysaccharide and Escherichia coli challenge but have opposite effects on survival. J. Infect. Dis. 193:829–40 [Google Scholar]
  52. Cui X, Moayeri M, Li Y, Li X, Haley M. 52.  et al. 2004. Lethality during continuous anthrax lethal toxin infusion is associated with circulatory shock but not inflammatory cytokine or nitric oxide release in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286:R699–709 [Google Scholar]
  53. Cunningham K, Lacy DB, Mogridge J, Collier RJ. 53.  2002. Mapping the lethal factor and edema factor binding sites on oligomeric anthrax protective antigen. PNAS 99:7049–53 [Google Scholar]
  54. D'Agnillo F, Williams MC, Moayeri M, Warfel JM. 54.  2013. Anthrax lethal toxin downregulates claudin-5 expression in human endothelial tight junctions. PLOS ONE 8:e62576 [Google Scholar]
  55. Dai Z, Sirard JC, Mock M, Koehler TM. 55.  1995. The atxA gene product activates transcription of the anthrax toxin genes and is essential for virulence. Mol. Microbiol. 16:1171–81 [Google Scholar]
  56. Dal Molin F, Fasanella A, Simonato M, Garofolo G, Montecucco C, Tonello F. 56.  2008. Ratio of lethal and edema factors in rabbit systemic anthrax. Toxicon 52:824–28 [Google Scholar]
  57. Dalldorf FG, Beall FA. 57.  1967. Capillary thrombosis as a cause of death in experimental anthrax. Arch. Pathol. 83:154–61 [Google Scholar]
  58. Drobniewski FA. 58.  1993. Bacillus cereus and related species. Clin. Microbiol. Rev. 6:324–38 [Google Scholar]
  59. Drum CL, Yan SZ, Bard J, Shen YQ, Lu D. 59.  et al. 2002. Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin. Nature 415:396–402 [Google Scholar]
  60. Drysdale M, Bourgogne A, Hilsenbeck SG, Koehler TM. 60.  2004. atxA controls Bacillus anthracis capsule synthesis via acpA and a newly discovered regulator, acpB. J. Bacteriol. 186:307–15 [Google Scholar]
  61. Drysdale M, Bourgogne A, Koehler TM. 61.  2005. Transcriptional analysis of the Bacillus anthracis capsule regulators. J. Bacteriol. 187:5108–14 [Google Scholar]
  62. Drysdale M, Heninger S, Hutt J, Chen Y, Lyons CR, Koehler TM. 62.  2005. Capsule synthesis by Bacillus anthracis is required for dissemination in murine inhalation anthrax. EMBO J. 24:221–27 [Google Scholar]
  63. Duesbery NS, Webb CP, Leppla SH, Gordon VM, Klimpel KR. 63.  et al. 1998. Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science 280:734–37 [Google Scholar]
  64. During RL, Gibson BG, Li W, Bishai EA, Sidhu GS. 64.  et al. 2007. Anthrax lethal toxin paralyzes actin-based motility by blocking Hsp27 phosphorylation. EMBO J. 26:2240–50 [Google Scholar]
  65. During RL, Li W, Hao B, Koenig JM, Stephens DS. 65.  et al. 2005. Anthrax lethal toxin paralyzes neutrophil actin-based motility. J. Infect. Dis. 192:837–45 [Google Scholar]
  66. Ebrahimi CM, Sheen TR, Renken CW, Gottlieb RA, Doran KS. 66.  2011. Contribution of lethal toxin and edema toxin to the pathogenesis of anthrax meningitis. Infect. Immun. 79:2510–18 [Google Scholar]
  67. Erwin JL, DaSilva LM, Bavari S, Little SF, Friedlander AM, Chanh TC. 67.  2001. Macrophage-derived cell lines do not express proinflammatory cytokines after exposure to Bacillus anthracis lethal toxin. Infect. Immun. 69:1175–77 [Google Scholar]
  68. Feinen B, Petrovsky N, Verma A, Merkel TJ. 68.  2014. Advax-adjuvanted recombinant protective antigen provides protection against inhalational anthrax that is further enhanced by addition of murabutide adjuvant. Clin. Vaccine Immunol. 21:580–86 [Google Scholar]
  69. Feld GK, Brown MJ, Krantz BA. 69.  2012. Ratcheting up protein translocation with anthrax toxin. Protein Sci. 21:606–24 [Google Scholar]
  70. Firoved AM, Miller GF, Moayeri M, Kakkar R, Shen Y. 70.  et al. 2005. Bacillus anthracis edema toxin causes extensive tissue lesions and rapid lethality in mice. Am. J. Pathol. 167:1309–20 [Google Scholar]
  71. Fish DC, Klein F, Lincoln RE, Walker JS, Dobbs JP. 71.  1968. Pathophysiological changes in the rat associated with anthrax toxin. J. Infect. Dis. 118:114–24 [Google Scholar]
  72. Fish DC, Lincoln RE. 72.  1967. Biochemical and biophysical characterization of anthrax toxin. Fed. Proc. 26:1534–38 [Google Scholar]
  73. Fish DC, Lincoln RE. 73.  1968. In vivo-produced anthrax toxin. J. Bacteriol. 95:919–24 [Google Scholar]
  74. Fouet A. 74.  2010. AtxA, a Bacillus anthracis global virulence regulator. Res. Microbiol. 161:735–42 [Google Scholar]
  75. Friedlander AM. 75.  1986. Macrophages are sensitive to anthrax lethal toxin through an acid-dependent process. J. Biol. Chem. 261:7123–26 [Google Scholar]
  76. Friedlander AM, Little SF. 76.  2009. Advances in the development of next-generation anthrax vaccines. Vaccine 27:Suppl. 4D28–32 [Google Scholar]
  77. Froude JW, Thullier P, Pelat T. 77.  2011. Antibodies against anthrax: mechanisms of action and clinical applications. Toxins 3:1433–52 [Google Scholar]
  78. Garcia AA, Fels RJ, Mosher LJ, Kenney MJ. 78.  2012. Bacillus anthracis lethal toxin alters regulation of visceral sympathetic nerve discharge. J. Appl. Physiol. 112:1033–40 [Google Scholar]
  79. Garufi G, Wang YT, Oh SY, Maier H, Missiakas DM, Schneewind O. 79.  2012. Sortase-conjugation generates a capsule vaccine that protects guinea pigs against Bacillus anthracis. Vaccine 30:3435–44 [Google Scholar]
  80. Gat O, Grosfeld H, Ariel N, Inbar I, Zaide G. 80.  et al. 2006. Search for Bacillus anthracis potential vaccine candidates by a functional genomic-serologic screen. Infect. Immun. 74:3987–4001 [Google Scholar]
  81. Gat O, Mendelson I, Chitlaru T, Ariel N, Altboum Z. 81.  et al. 2005. The solute-binding component of a putative Mn(II) ABC transporter (MntA) is a novel Bacillus anthracis virulence determinant. Mol. Microbiol. 58:533–51 [Google Scholar]
  82. Gat O, Zaide G, Inbar I, Grosfeld H, Chitlaru T. 82.  et al. 2008. Characterization of Bacillus anthracis iron-regulated surface determinant (Isd) proteins containing NEAT domains. Mol. Microbiol. 70:983–99 [Google Scholar]
  83. Gleiser CA. 83.  1967. Pathology of anthrax infection in animal hosts. Fed. Proc. 26:1518–21 [Google Scholar]
  84. Gleiser CA, Berdjis CC, Hartman HA, Gochenour WS. 84.  1963. Pathology of experimental respiratory anthrax in Macaca mulatta. Br. J. Exp. Pathol. 44:416–26 [Google Scholar]
  85. Gohar M, Faegri K, Perchat S, Ravnum S, Okstad OA. 85.  et al. 2008. The PlcR virulence regulon of Bacillus cereus. PLOS ONE 3:e2793 [Google Scholar]
  86. Gorse GJ, Keitel W, Keyserling H, Taylor DN, Lock M. 86.  et al. 2006. Immunogenicity and tolerance of ascending doses of a recombinant protective antigen (rPA102) anthrax vaccine: a randomized, double-blinded, controlled, multicenter trial. Vaccine 24:5950–59 [Google Scholar]
  87. Guichard A, McGillivray SM, Cruz-Moreno B, van Sorge NM, Nizet V, Bier E. 87.  2010. Anthrax toxins cooperatively inhibit endocytic recycling by the Rab11/Sec15 exocyst. Nature 467:854–58 [Google Scholar]
  88. Guichard A, Nizet V, Bier E. 88.  2011. New insights into the biological effects of anthrax toxins: linking cellular to organismal responses. Microbes Infect. 14:97–118 [Google Scholar]
  89. Guichard A, Park JM, Cruz-Moreno B, Karin M, Bier E. 89.  2006. Anthrax lethal factor and edema factor act on conserved targets in Drosophila. PNAS 103:3244–49 [Google Scholar]
  90. Guignot J, Mock M, Fouet A. 90.  1997. AtxA activates the transcription of genes harbored by both Bacillus anthracis virulence plasmids. FEMS Microbiol. Lett. 147:203–7 [Google Scholar]
  91. Guo Q, Shen Y, Zhukovskaya NL, Florian J, Tang WJ. 91.  2004. Structural and kinetic analyses of the interaction of anthrax adenylyl cyclase toxin with reaction products cAMP and pyrophosphate. J. Biol. Chem. 279:29427–35 [Google Scholar]
  92. Hammerstrom TG, Roh J, Nikonowicz EP, Koehler TM. 92.  2011. Bacillus anthracis virulence regulator AtxA: oligomeric state, function, and CO2-signalling. Mol. Microbiol. 82:634–47 [Google Scholar]
  93. Harrell LJ, Andersen GL, Wilson KH. 93.  1995. Genetic variability of Bacillus anthracis and related species. J. Clin. Microbiol. 33:1847–50 [Google Scholar]
  94. Heffernan BJ, Thomason B, Herring-Palmer A, Hanna P. 94.  2007. Bacillus anthracis anthrolysin O and three phospholipases C are functionally redundant in a murine model of inhalation anthrax. FEMS Microbiol. Lett. 271:98–105 [Google Scholar]
  95. Helgason E, Okstad OA, Caugant DA, Johansen HA, Fouet A. 95.  et al. 2000. Bacillus anthracis, Bacillus cereus, and Bacillus thuringiensis—one species on the basis of genetic evidence. Appl. Environ. Microbiol. 66:2627–30 [Google Scholar]
  96. Hellmich KA, Levinsohn JL, Fattah R, Newman ZL, Maier N. 96.  et al. 2012. Anthrax lethal factor cleaves mouse Nlrp1b in both toxin-sensitive and toxin-resistant macrophages. PLOS ONE 7:e49741 [Google Scholar]
  97. Hicks CW, Li Y, Okugawa S, Solomon SB, Moayeri M. 97.  et al. 2011. Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model. Am. J. Physiol. Heart Circ. Physiol. 300:H1108–18 [Google Scholar]
  98. Hoffmaster AR, Hill KK, Gee JE, Marston CK, De BK. 98.  et al. 2006. Characterization of Bacillus cereus isolates associated with fatal pneumonias: Strains are closely related to Bacillus anthracis and harbor B. anthracis virulence genes. J. Clin. Microbiol. 44:3352–60 [Google Scholar]
  99. Hoffmaster AR, Ravel J, Rasko DA, Chapman GD, Chute MD. 99.  et al. 2004. Identification of anthrax toxin genes in a Bacillus cereus associated with an illness resembling inhalation anthrax. PNAS 101:8449–54 [Google Scholar]
  100. Hopkins RJ, Howard C, Hunter-Stitt E, Kaptur PE, Pleune B. 100.  et al. 2014. Phase 3 trial evaluating the immunogenicity and safety of a three-dose BioThrax® regimen for post-exposure prophylaxis in healthy adults. Vaccine 32:2217–24 [Google Scholar]
  101. Hu H, Sa Q, Koehler TM, Aronson AI, Zhou D. 101.  2006. Inactivation of Bacillus anthracis spores in murine primary macrophages. Cell. Microbiol. 8:1634–42 [Google Scholar]
  102. Hu X, Van der Auwera G, Timmery S, Zhu L, Mahillon J. 102.  2009. Distribution, diversity and potential mobility of extra-chromosomal elements related to the Bacillus anthracis pXO1 and pXO2 virulence plasmids. Appl. Environ. Microbiol. 75:3016–28 [Google Scholar]
  103. Hutt JA, Lovchik JA, Drysdale M, Sherwood RL, Brasel T. 103.  et al. 2014. Lethal factor, but not edema factor, is required to cause fatal anthrax in cynomolgus macaques after pulmonary spore challenge. Am. J. Pathol. 184:3205–16 [Google Scholar]
  104. Ivins BE, Pitt ML, Fellows PF, Farchaus JW, Benner GE. 104.  et al. 1998. Comparative efficacy of experimental anthrax vaccine candidates against inhalation anthrax in rhesus macaques. Vaccine 16:1141–48 [Google Scholar]
  105. Jelacic TM, Chabot DJ, Bozue JA, Tobery SA, West MW. 105.  et al. 2014. Exposure to Bacillus anthracis capsule results in suppression of human monocyte-derived dendritic cells. Infect. Immun. 82:3405–16 [Google Scholar]
  106. Jenkins A, Cote C, Twenhafel N, Merkel T, Bozue J, Welkos S. 106.  2010. Role of purine biosynthesis in Bacillus anthracis pathogenesis and virulence. Infect. Immun. 79:153–66 [Google Scholar]
  107. Jenkins SA, Xu Y. 107.  2013. Characterization of Bacillus anthracis persistence in vivo. PLOS ONE 8:e66177 [Google Scholar]
  108. Jernigan JA, Stephens DS, Ashford DA, Omenaca C, Topiel MS. 108.  et al. 2001. Bioterrorism-related inhalational anthrax: the first 10 cases reported in the United States. Emerg. Infect. Dis. 7:933–44 [Google Scholar]
  109. Jiao GS, Kim S, Moayeri M, Cregar-Hernandez L, McKasson L. 109.  et al. 2010. Antidotes to anthrax lethal factor intoxication. Part 1: Discovery of potent lethal factor inhibitors with in vivo efficacy. Bioorg. Med. Chem. Lett. 20:6850–53 [Google Scholar]
  110. Jiao GS, Kim S, Moayeri M, Crown D, Thai A. 110.  et al. 2012. Antidotes to anthrax lethal factor intoxication. Part 3: Evaluation of core structures and further modifications to the C2-side chain. Bioorg. Med. Chem. Lett. 22:2242–46 [Google Scholar]
  111. Jones WI Jr, Klein F, Walker JS, Mahlandt BG, Dobbs JP, Lincoln RE. 111.  1967. In vivo growth and distribution of anthrax bacilli in resistant, susceptible, and immunized hosts. J. Bacteriol. 94:600–8 [Google Scholar]
  112. Joyce JG, Cook J, Chabot D, Hepler R, Shoop W. 112.  et al. 2006. Immunogenicity and protective efficacy of Bacillus anthracis poly-γ-d-glutamic acid capsule covalently coupled to a protein carrier using a novel triazine-based conjugation strategy. J. Biol. Chem. 281:4831–43 [Google Scholar]
  113. Kandadi MR, Hua Y, Ma H, Li Q, Kuo SR. 113.  et al. 2010. Anthrax lethal toxin suppresses murine cardiomyocyte contractile function and intracellular Ca2+ handling via a NADPH oxidase-dependent mechanism. PLOS ONE 5:e13335 [Google Scholar]
  114. Karginov VA, Nestorovich EM, Moayeri M, Leppla SH, Bezrukov SM. 114.  2005. Blocking anthrax lethal toxin at the protective antigen channel by using structure-inspired drug design. PNAS 102:15075–80 [Google Scholar]
  115. Kau JH, Sun DS, Huang HS, Lien TS, Huang HH. 115.  et al. 2010. Sublethal doses of anthrax lethal toxin on the suppression of macrophage phagocytosis. PLOS ONE 5:e14289 [Google Scholar]
  116. Kaur M, Singh S, Bhatnagar R. 116.  2013. Anthrax vaccines: present status and future prospects. Expert. Rev. Vaccines 12:955–70 [Google Scholar]
  117. Keim P, Price LB, Klevytska AM, Smith KL, Schupp JM. 117.  et al. 2000. Multiple-locus variable-number tandem repeat analysis reveals genetic relationships within Bacillus anthracis. J. Bacteriol. 182:2928–36 [Google Scholar]
  118. Keitel WA. 118.  2006. Recombinant protective antigen 102 (rPA102): profile of a second-generation anthrax vaccine. Expert Rev. Vaccines 5:417–30 [Google Scholar]
  119. Kern J, Schneewind O. 119.  2010. BslA, the S-layer adhesin of B. anthracis, is a virulence factor for anthrax pathogenesis. Mol. Microbiol. 75:324–32 [Google Scholar]
  120. Kim C, Wilcox-Adelman S, Sano Y, Tang WJ, Collier RJ, Park JM. 120.  2008. Antiinflammatory cAMP signaling and cell migration genes co-opted by the anthrax bacillus. PNAS 105:6150–55 [Google Scholar]
  121. Kim S, Jiao GS, Moayeri M, Crown D, Cregar-Hernandez L. 121.  et al. 2011. Antidotes to anthrax lethal factor intoxication. Part 2: structural modifications leading to improved in vivo efficacy. Bioorg. Med. Chem. Lett. 21:2030–33 [Google Scholar]
  122. Kintzer AF, Thoren KL, Sterling HJ, Dong KC, Feld GK. 122.  et al. 2009. The protective antigen component of anthrax toxin forms functional octameric complexes. J. Mol. Biol. 392:614–29 [Google Scholar]
  123. Klee SR, Ozel M, Appel B, Boesch C, Ellerbrok H. 123.  et al. 2006. Characterization of Bacillus anthracis-like bacteria isolated from wild great apes from Côte d'Ivoire and Cameroon. J. Bacteriol. 188:5333–44 [Google Scholar]
  124. Klein F, Hodges DR, Mahlandt BG, Jones WI, Haines BW, Lincoln RE. 124.  1962. Anthrax toxin: causative agent in the death of rhesus monkeys. Science 138:1331–33 [Google Scholar]
  125. Klein F, Walker JS, Fitzpatrick DF, Lincoln RE, Mahlandt BG. 125.  et al. 1966. Pathophysiology of anthrax. J. Infect. Dis. 116:123–38 [Google Scholar]
  126. Klimpel KR, Arora N, Leppla SH. 126.  1994. Anthrax toxin lethal factor contains a zinc metalloprotease consensus sequence which is required for lethal toxin activity. Mol. Microbiol. 13:1093–100 [Google Scholar]
  127. Klimpel KR, Leppla SH, Singh Y, Quinn CP. 127.  1992. Fine structure analysis of the amino acid sequence recognized by the eukaryotic cell protease that activates anthrax toxin. Bacterial Protein Toxins B Witholt, JE Alouf, GJ Boulnois, P Cossart, BW Dijkstra 490–91 Stuttgart, Germ: Gustav Fischer [Google Scholar]
  128. Koehler TM, Dai Z, Kaufman-Yarbray M. 128.  1994. Regulation of the Bacillus anthracis protective antigen gene: CO2 and a trans-acting element activate transcription from one of two promoters. J. Bacteriol. 176:586–95 [Google Scholar]
  129. Koppisch AT, Browder CC, Moe AL, Shelley JT, Kinkel BA. 129.  et al. 2005. Petrobactin is the primary siderophore synthesized by Bacillus anthracis str. Sterne under conditions of iron starvation. Biometals 18:577–85 [Google Scholar]
  130. Kozel TR, Thorkildson P, Brandt S, Welch WH, Lovchik JA. 130.  et al. 2007. Protective and immunochemical activities of monoclonal antibodies reactive with the Bacillus anthracis polypeptide capsule. Infect. Immun. 75:152–63 [Google Scholar]
  131. Krantz BA, Finkelstein A, Collier RJ. 131.  2005. Protein translocation through the anthrax toxin transmembrane pore is driven by a proton gradient. J. Mol. Biol. 355:968–79 [Google Scholar]
  132. Krantz BA, Melnyk RA, Zhang S, Juris SJ, Lacy DB. 132.  et al. 2005. A phenylalanine clamp catalyzes protein translocation through the anthrax toxin pore. Science 309:777–81 [Google Scholar]
  133. Kuo SR, Willingham MC, Bour SH, Andreas EA, Park SK. 133.  et al. 2008. Anthrax toxin-induced shock in rats is associated with pulmonary edema and hemorrhage. Microb. Pathog. 44:467–72 [Google Scholar]
  134. Lacy DB, Mourez M, Fouassier A, Collier RJ. 134.  2002. Mapping the anthrax protective antigen binding site on the lethal and edema factors. J. Biol. Chem. 277:3006–10 [Google Scholar]
  135. Langer M, Duggan ES, Booth JL, Patel VI, Zander RA. 135.  et al. 2012. Bacillus anthracis lethal toxin reduces human alveolar epithelial barrier function. Infect. Immun. 80:4374–87 [Google Scholar]
  136. Leffel EK, Bourdage JS, Williamson ED, Duchars M, Fuerst TR, Fusco PC. 136.  2012. Recombinant protective antigen anthrax vaccine improves survival when administered as a postexposure prophylaxis countermeasure with antibiotic in the New Zealand white rabbit model of inhalation anthrax. Clin. Vaccine Immunol. 19:1158–64 [Google Scholar]
  137. Lehmann M, Noack D, Wood M, Perego M, Knaus UG. 137.  2009. Lung epithelial injury by B. anthracis lethal toxin is caused by MKK-dependent loss of cytoskeletal integrity. PLOS ONE 4:e4755 [Google Scholar]
  138. Leppla SH. 138.  1982. Anthrax toxin edema factor: a bacterial adenylate cyclase that increases cyclic AMP concentrations of eukaryotic cells. PNAS 79:3162–66 [Google Scholar]
  139. Leppla SH. 139.  1984. Bacillus anthracis calmodulin-dependent adenylate cyclase: chemical and enzymatic properties and interactions with eucaryotic cells. Adv. Cycl. Nucleotide Protein Phosphorylation Res. 17:189–98 [Google Scholar]
  140. Levinsohn JL, Newman ZL, Hellmich KA, Fattah R, Getz MA. 140.  et al. 2012. Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome. PLOS Pathog. 8:e1002638 [Google Scholar]
  141. Levy H, Glinert I, Weiss S, Sittner A, Schlomovitz J. 141.  et al. 2014. Toxin-independent virulence of Bacillus anthracis in rabbits. PLOS ONE 9:e84947 [Google Scholar]
  142. Levy H, Weiss S, Altboum Z, Schlomovitz J, Glinert I. 142.  et al. 2012. Differential contribution of Bacillus anthracis toxins to pathogenicity in two animal models. Infect. Immun. 80:2623–31 [Google Scholar]
  143. Levy H, Weiss S, Altboum Z, Schlomovitz J, Rothschild N. 143.  et al. 2011. Lethal factor is not required for Bacillus anthracis virulence in guinea pigs and rabbits. Microb. Pathog. 51:345–51 [Google Scholar]
  144. Levy H, Weiss S, Altboum Z, Schlomovitz J, Rothschild N. 144.  et al. 2011. The effect of deletion of the edema factor on Bacillus anthracis pathogenicity in guinea pigs and rabbits. Microb. Pathog. 52:55–60 [Google Scholar]
  145. Li Y, Cui X, Su J, Haley M, Macarthur H. 145.  et al. 2009. Norepinephrine increases blood pressure but not survival with anthrax lethal toxin in rats. Crit. Care Med. 37:1348–54 [Google Scholar]
  146. Lincoln RE, Hodges DR, Klein F, Mahlandt BG, Jones WI Jr. 146.  et al. 1965. Role of the lymphatics in the pathogenesis of anthrax. J. Infect. Dis. 115:481–94 [Google Scholar]
  147. Lincoln RE, Walker JS, Klein F, Rosenwald AJ, Jones WI Jr. 147.  1967. Value of field data for extrapolation in anthrax. Fed. Proc. 26:1558–62 [Google Scholar]
  148. Little SF, Ivins BE, Fellows PF, Pitt ML, Norris SL, Andrews GP. 148.  2004. Defining a serological correlate of protection in rabbits for a recombinant anthrax vaccine. Vaccine 22:422–30 [Google Scholar]
  149. Liu S, Crown D, Miller-Randolph S, Moayeri M, Wang H. 149.  et al. 2009. Capillary morphogenesis protein-2 is the major receptor mediating lethality of anthrax toxin in vivo. PNAS 106:12424–29 [Google Scholar]
  150. Liu S, Leppla SH. 150.  2003. Cell surface tumor endothelium marker 8 cytoplasmic tail-independent anthrax toxin binding, proteolytic processing, oligomer formation, and internalization. J. Biol. Chem. 278:5227–34 [Google Scholar]
  151. Liu S, Leung HJ, Leppla SH. 151.  2007. Characterization of the interaction between anthrax toxin and its cellular receptors. Cell. Microbiol. 9:977–87 [Google Scholar]
  152. Liu S, Miller-Randolph S, Crown D, Moayeri M, Sastalla I. 152.  et al. 2010. Anthrax toxin targeting of myeloid cells through the CMG2 receptor is essential for establishment of Bacillus anthracis infections in mice. Cell Host Microbe 8:455–62 [Google Scholar]
  153. Liu S, Zhang Y, Moayeri M, Liu J, Crown D. 153.  et al. 2013. Key tissue targets responsible for anthrax-toxin-induced lethality. Nature 501:63–68 [Google Scholar]
  154. Lovchik JA, Drysdale M, Koehler TM, Hutt JA, Lyons CR. 154.  2012. Expression of either lethal toxin or edema toxin by Bacillus anthracis is sufficient for virulence in a rabbit model of inhalational anthrax. Infect. Immun. 80:2414–25 [Google Scholar]
  155. Lowe DE, Glomski IJ. 155.  2012. Cellular and physiological effects of anthrax exotoxin and its relevance to disease. Front. Cell Infect. Microbiol. 2:76 [Google Scholar]
  156. Mabry R, Brasky K, Geiger R, Carrion R Jr, Hubbard GB. 156.  et al. 2006. Detection of anthrax toxin in the serum of animals infected with Bacillus anthracis by using engineered immunoassays. Clin. Vaccine Immunol. 13:671–77 [Google Scholar]
  157. Makino S, Uchida I, Terakado N, Sasakawa C, Yoshikawa M. 157.  1989. Molecular characterization and protein analysis of the cap region, which is essential for encapsulation in Bacillus anthracis. J. Bacteriol. 171:722–30 [Google Scholar]
  158. Makino S, Watarai M, Cheun HI, Shirahata T, Uchida I. 158.  2002. Effect of the lower molecular capsule released from the cell surface of Bacillus anthracis on the pathogenesis of anthrax. J. Infect. Dis. 186:227–33 [Google Scholar]
  159. Maresso AW, Garufi G, Schneewind O. 159.  2008. Bacillus anthracis secretes proteins that mediate heme acquisition from hemoglobin. PLOS Pathog. 4:e1000132 [Google Scholar]
  160. McGillivray SM, Ebrahimi CM, Fisher N, Sabet M, Zhang DX. 160.  et al. 2009. ClpX contributes to innate defense peptide resistance and virulence phenotypes of Bacillus anthracis. J. Innate Immun. 1:494–506 [Google Scholar]
  161. McKenzie AT, Pomerantsev AP, Sastalla I, Martens C, Ricklefs SM. 161.  et al. 2014. Transcriptome analysis identifies Bacillus anthracis genes that respond to CO2 through an AtxA-dependent mechanism. BMC Genomics 15:229 [Google Scholar]
  162. Meselson M, Guillemin J, Hugh-Jones M, Langmuir A, Popova I. 162.  et al. 1994. The Sverdlovsk anthrax outbreak of 1979. Science 266:1202–8 [Google Scholar]
  163. Migone TS, Subramanian GM, Zhong J, Healey LM, Corey A. 163.  et al. 2009. Raxibacumab for the treatment of inhalational anthrax. N. Engl. J. Med. 361:135–44 [Google Scholar]
  164. Miller CJ, Elliott JL, Collier RJ. 164.  1999. Anthrax protective antigen: prepore-to-pore conversion. Biochemistry 38:10432–41 [Google Scholar]
  165. Milne JC, Collier RJ. 165.  1993. pH-dependent permeabilization of the plasma membrane of mammalian cells by anthrax protective antigen. Mol. Microbiol. 10:647–53 [Google Scholar]
  166. Milne JC, Furlong D, Hanna PC, Wall JS, Collier RJ. 166.  1994. Anthrax protective antigen forms oligomers during intoxication of mammalian cells. J. Biol. Chem. 269:20607–12 [Google Scholar]
  167. Moayeri M, Crown D, Dorward DW, Gardner D, Ward JM. 167.  et al. 2009. The heart is an early target of anthrax lethal toxin in mice: a protective role for neuronal nitric oxide synthase (nNOS). PLOS Pathog. 4:e1000456 [Google Scholar]
  168. Moayeri M, Crown D, Jiao GS, Kim S, Johnson A. 168.  et al. 2013. Small molecule inhibitors of lethal factor protease activity protect against anthrax infection. Antimicrob. Agents Chemother. 57:4139–45 [Google Scholar]
  169. Moayeri M, Crown D, Newman ZL, Okugawa S, Eckhaus M. 169.  et al. 2010. Inflammasome sensor Nlrp1b-dependent resistance to anthrax is mediated by caspase-1, IL-1 signaling and neutrophil recruitment. PLOS Pathog. 6:e1001222 [Google Scholar]
  170. Moayeri M, Haines D, Young HA, Leppla SH. 170.  2003. Bacillus anthracis lethal toxin induces TNF-α–independent hypoxia-mediated toxicity in mice. J. Clin. Investig. 112:670–82 [Google Scholar]
  171. Moayeri M, Leppla SH. 171.  2009. Cellular and systemic effects of anthrax lethal toxin and edema toxin. Mol. Aspects Med. 30:439–55 [Google Scholar]
  172. Moayeri M, Martinez NW, Wiggins J, Young HA, Leppla SH. 172.  2004. Mouse susceptibility to anthrax lethal toxin is influenced by genetic factors in addition to those controlling macrophage sensitivity. Infect. Immun. 72:4439–47 [Google Scholar]
  173. Moayeri M, Sastalla I, Leppla SH. 173.  2011. Anthrax and the inflammasome. Microbes Infect. 14:392–400 [Google Scholar]
  174. Moayeri M, Webster JI, Wiggins JF, Leppla SH, Sternberg EM. 174.  2005. Endocrine perturbation increases susceptibility of mice to anthrax lethal toxin. Infect. Immun. 73:4238–44 [Google Scholar]
  175. Mogridge J, Cunningham K, Collier RJ. 175.  2002. Stoichiometry of anthrax toxin complexes. Biochemistry 41:1079–82 [Google Scholar]
  176. Mogridge J, Cunningham K, Lacy DB, Mourez M, Collier RJ. 176.  2002. The lethal and edema factors of anthrax toxin bind only to oligomeric forms of the protective antigen. PNAS 99:7045–48 [Google Scholar]
  177. Mogridge J, Mourez M, Collier RJ. 177.  2001. Involvement of domain 3 in oligomerization by the protective antigen moiety of anthrax toxin. J. Bacteriol. 183:2111–16 [Google Scholar]
  178. Mourez M, Kane RS, Mogridge J, Metallo S, Deschatelets P. 178.  et al. 2001. Designing a polyvalent inhibitor of anthrax toxin. Nat. Biotechnol. 19:958–61 [Google Scholar]
  179. Muehlbauer SM, Evering TH, Bonuccelli G, Squires RC, Ashton AW. 179.  et al. 2007. Anthrax lethal toxin kills macrophages in a strain-specific manner by apoptosis or caspase-1-mediated necrosis. Cell Cycle 6:758–66 [Google Scholar]
  180. Nestorovich EM, Bezrukov SM. 180.  2012. Obstructing toxin pathways by targeted pore blockage. Chem. Rev. 112:6388–6430 [Google Scholar]
  181. Nestorovich EM, Bezrukov SM. 181.  2014. Designing inhibitors of anthrax toxin. Expert. Opin. Drug Discov. 9:299–318 [Google Scholar]
  182. Newman ZL, Printz MP, Liu S, Crown D, Breen L. 182.  et al. 2010. Susceptibility to anthrax lethal toxin-induced rat death is controlled by a single chromosome 10 locus that includes rNlrp1. PLOS Pathog. 6:e1000906 [Google Scholar]
  183. Nordberg BK, Schmiterlow CG, Hansen HJ. 183.  1961. Pathophysiological investigations into the terminal course of experimental anthrax in the rabbit. Acta Pathol. Microbiol. Scand. 53:295–318 [Google Scholar]
  184. O'Brien J, Friedlander A, Dreier T, Ezzell J, Leppla SH. 184.  1985. Effects of anthrax toxin components on human neutrophils. Infect. Immun. 47:306–10 [Google Scholar]
  185. Okinaka RT, Cloud K, Hampton O, Hoffmaster AR, Hill KK. 185.  et al. 1999. Sequence and organization of pXO1, the large Bacillus anthracis plasmid harboring the anthrax toxin genes. J. Bacteriol. 181:6509–15 [Google Scholar]
  186. Okugawa S, Moayeri M, Eckhaus MA, Crown D, Miller-Randolph S. 186.  et al. 2011. MyD88-dependent signaling protects against anthrax lethal toxin-induced impairment of intestinal barrier function. Infect. Immun. 79:118–24 [Google Scholar]
  187. Opal SM, Artenstein AW, Cristofaro PA, Jhung JW, Palardy JE. 187.  et al. 2005. Inter-alpha-inhibitor proteins are endogenous furin inhibitors and provide protection against experimental anthrax intoxication. Infect. Immun. 73:5101–5 [Google Scholar]
  188. Oscherwitz J, Yu F, Cease KB. 188.  2010. A synthetic peptide vaccine directed against the 2β2-2β3 loop of domain 2 of protective antigen protects rabbits from inhalation anthrax. J. Immunol. 185:3661–68 [Google Scholar]
  189. Oscherwitz J, Yu F, Jacobs JL, Cease KB. 189.  2013. Recombinant vaccine displaying the loop-neutralizing determinant from protective antigen completely protects rabbits from experimental inhalation anthrax. Clin. Vaccine Immunol. 20:341–49 [Google Scholar]
  190. Paccani SR, Tonello F, Patrussi L, Capitani N, Simonato M. 190.  et al. 2007. Anthrax toxins inhibit immune cell chemotaxis by perturbing chemokine receptor signalling. Cell. Microb. 9:924–29 [Google Scholar]
  191. Pannifer AD, Wong TY, Schwarzenbacher R, Renatus M, Petosa C. 191.  et al. 2001. Crystal structure of the anthrax lethal factor. Nature 414:229–33 [Google Scholar]
  192. Pannucci J, Okinaka RT, Sabin R, Kuske CR. 192.  2002. Bacillus anthracis pXO1 plasmid sequence conservation among closely related bacterial species. J. Bacteriol. 184:134–41 [Google Scholar]
  193. Park JM, Greten FR, Li ZW, Karin M. 193.  2002. Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science 297:2048–51 [Google Scholar]
  194. Pellizzari R, Guidi-Rontani C, Vitale G, Mock M, Montecucco C. 194.  2000. Lethal factor of Bacillus anthracis cleaves the N-terminus of MAPKKs: analysis of the intracellular consequences in macrophages. Int. J. Med. Microbiol. 290:421–27 [Google Scholar]
  195. Perez CR, Lopez-Perez D, Chmielewski J, Lipton M. 195.  2012. Small molecule inhibitors of anthrax toxin-induced cytotoxicity targeted against protective antigen. Chem. Biol. Drug Des. 79:260–69 [Google Scholar]
  196. Petosa C, Collier RJ, Klimpel KR, Leppla SH, Liddington RC. 196.  1997. Crystal structure of the anthrax toxin protective antigen. Nature 385:833–38 [Google Scholar]
  197. Pezard C, Berche P, Mock M. 197.  1991. Contribution of individual toxin components to virulence of Bacillus anthracis. Infect. Immun. 59:3472–77 [Google Scholar]
  198. Pitt ML, Little SF, Ivins BE, Fellows P, Barth J. 198.  et al. 2001. In vitro correlate of immunity in a rabbit model of inhalational anthrax. Vaccine 19:4768–73 [Google Scholar]
  199. Pomerantsev AP, Camp A, Leppla SH. 199.  2009. A new minimal replicon of Bacillus anthracis plasmid pXO1. J. Bacteriol. 191:5134–46 [Google Scholar]
  200. Pomerantsev AP, Chang Z, Rappole C, Leppla SH. 200.  2014. Identification of three noncontiguous regions on Bacillus anthracis plasmid pXO1 that are important for its maintenance. J. Bacteriol. 196:2921–33 [Google Scholar]
  201. Quinn CP, Sabourin CL, Niemuth NA, Li H, Semenova VA. 201.  et al. 2012. A three dose intramuscular schedule of anthrax vaccine adsorbed generates sustained humoral and cellular immune responses to protective antigen and provides long term protection against inhalation anthrax in rhesus macaques. Clin. Vaccine Immunol. 19:1730–45 [Google Scholar]
  202. Rainey GJ, Wigelsworth DJ, Ryan PL, Scobie HM, Collier RJ, Young JA. 202.  2005. Receptor-specific requirements for anthrax toxin delivery into cells. PNAS 102:13278–83 [Google Scholar]
  203. Ramsay CN, Stirling A, Smith J, Hawkins G, Brooks T. 203.  et al. 2010. An outbreak of infection with Bacillus anthracis in injecting drug users in Scotland. Euro. Surveill. 15:19465 [Google Scholar]
  204. Rasko DA, Altherr MR, Han CS, Ravel J. 204.  2005. Genomics of the Bacillus cereus group of organisms. FEMS Microbiol. Rev. 29:303–29 [Google Scholar]
  205. Rasko DA, Ravel J, Okstad OA, Helgason E, Cer RZ. 205.  et al. 2004. The genome sequence of Bacillus cereus ATCC 10987 reveals metabolic adaptations and a large plasmid related to Bacillus anthracis pXO1. Nucleic Acids Res. 32:977–88 [Google Scholar]
  206. Ravel J, Jiang L, Stanley ST, Wilson MR, Decker RS. 206.  et al. 2009. The complete genome sequence of Bacillus anthracis Ames “Ancestor”. J. Bacteriol. 191:445–46 [Google Scholar]
  207. Raymond B, Batsche E, Boutillon F, Wu YZ, Leduc D. 207.  et al. 2009. Anthrax lethal toxin impairs IL-8 expression in epithelial cells through inhibition of histone H3 modification. PLOS Pathog. 5:e1000359 [Google Scholar]
  208. Read TD, Salzberg SL, Pop M, Shumway M, Umayam L. 208.  et al. 2002. Comparative genome sequencing for discovery of novel polymorphisms in Bacillus anthracis. Science 296:2028–33 [Google Scholar]
  209. Reig N, Jiang A, Couture R, Sutterwala FS, Ogura Y. 209.  et al. 2008. Maturation modulates caspase-1-independent responses of dendritic cells to anthrax lethal toxin. Cell. Microbiol. 10:1190–207 [Google Scholar]
  210. Remacle AG, Gawlik K, Golubkov VS, Cadwell GW, Liddington RC. 210.  et al. 2010. Selective and potent furin inhibitors protect cells from anthrax without significant toxicity. Int. J. Biochem. Cell Biol. 42:987–95 [Google Scholar]
  211. Rhie GE, Roehrl MH, Mourez M, Collier RJ, Mekalanos JJ, Wang JY. 211.  2003. A dually active anthrax vaccine that confers protection against both bacilli and toxins. PNAS 100:10925–30 [Google Scholar]
  212. Ribot WJ, Panchal RG, Brittingham KC, Ruthel G, Kenny TA. 212.  et al. 2006. Anthrax lethal toxin impairs innate immune functions of alveolar macrophages and facilitates Bacillus anthracis survival. Infect. Immun. 74:5029–34 [Google Scholar]
  213. Richter S, Anderson VJ, Garufi G, Lu L, Budzik JM. 213.  et al. 2009. Capsule anchoring in Bacillus anthracis occurs by a transpeptidation reaction that is inhibited by capsidin. Mol. Microbiol. 71:404–20 [Google Scholar]
  214. Riddle V, Leese P, Blanset D, Adamcio M, Meldorf M, Lowy I. 214.  2011. Phase I study evaluating the safety and pharmacokinetics of MDX-1303, a fully human monoclonal antibody against Bacillus anthracis protective antigen, in healthy volunteers. Clin. Vaccine Immunol. 18:2136–42 [Google Scholar]
  215. Rolando M, Stefani C, Flatau G, Auberger P, Mettouchi A. 215.  et al. 2010. Transcriptome dysregulation by anthrax lethal toxin plays a key role in induction of human endothelial cell cytotoxicity. Cell. Microbiol. 12:891–905 [Google Scholar]
  216. Rosovitz MJ, Schuck P, Varughese M, Chopra AP, Mehra V. 216.  et al. 2003. Alanine scanning mutations in domain 4 of anthrax toxin protective antigen reveal residues important for binding to the cellular receptor and to a neutralizing monoclonal antibody. J. Biol. Chem. 278:30936–44 [Google Scholar]
  217. Ross JM. 217.  1955. On the histopathology of experimental anthrax in the guinea-pig. Br. J. Exp. Pathol. 36:336–39 [Google Scholar]
  218. Ross JM. 218.  1957. The pathogenesis of anthrax following administration of spores by the respiratory route. J. Pathol. Bacteriol. 73:485–94 [Google Scholar]
  219. Rynkiewicz D, Rathkopf M, Sim I, Waytes AT, Hopkins RJ. 219.  et al. 2011. Marked enhancement of the immune response to BioThrax® (Anthrax Vaccine Adsorbed) by the TLR9 agonist CPG 7909 in healthy volunteers. Vaccine 29:6313–20 [Google Scholar]
  220. Sastalla I, Maltese L, Pomerantseva OM, Pomerantsev AP, Keane-Myers A, Leppla SH. 220.  2010. Activation of the latent PlcR regulon in Bacillus anthracis. Microbiology 156:2982–93 [Google Scholar]
  221. Sastalla I, Tang S, Crown D, Liu S, Eckhaus MA. 221.  et al. 2011. Anthrax edema toxin impairs protein clearance in mice. Infect. Immun. 80:529–38 [Google Scholar]
  222. Schein CH, Chen D, Ma L, Kanalas JJ, Gao J. 222.  et al. 2012. Pharmacophore selection and redesign of non-nucleotide inhibitors of anthrax edema factor. Toxins 4:1288–300 [Google Scholar]
  223. Schneerson R, Kubler-Kielb J, Liu TY, Dai ZD, Leppla SH. 223.  et al. 2003. Poly(γ-d-glutamic acid) protein conjugates induce IgG antibodies in mice to the capsule of Bacillus anthracis: a potential addition to the anthrax vaccine. PNAS 100:8945–50 [Google Scholar]
  224. Scobie HM, Rainey GJ, Bradley KA, Young JA. 224.  2003. Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor. PNAS 100:5170–74 [Google Scholar]
  225. Scobie HM, Thomas D, Marlett JM, Destito G, Wigelsworth DJ. 225.  et al. 2005. A soluble receptor decoy protects rats against anthrax lethal toxin challenge. J. Infect. Dis. 192:1047–51 [Google Scholar]
  226. Scorpio A, Chabot DJ, Day WA, Hoover TA, Friedlander AM. 226.  2010. Capsule depolymerase overexpression reduces Bacillus anthracis virulence. Microbiology 156:1459–67 [Google Scholar]
  227. Scorpio A, Tobery SA, Ribot WJ, Friedlander AM. 227.  2008. Treatment of experimental anthrax with recombinant capsule depolymerase. Antimicrob. Agents Chemother. 52:1014–20 [Google Scholar]
  228. Seifert R, Dove S. 228.  2013. Inhibitors of Bacillus anthracis edema factor. Pharmacol. Ther. 140:200–12 [Google Scholar]
  229. Sellman BR, Mourez M, Collier RJ. 229.  2001. Dominant-negative mutants of a toxin subunit: an approach to therapy of anthrax. Science 292:695–97 [Google Scholar]
  230. Shannon JG, Ross CL, Koehler TM, Rest RF. 230.  2003. Characterization of anthrolysin O, the Bacillus anthracis cholesterol-dependent cytolysin. Infect. Immun. 71:3183–89 [Google Scholar]
  231. Sharma S, Thomas D, Marlett J, Manchester M, Young JA. 231.  2009. Efficient neutralization of antibody-resistant forms of anthrax toxin by a soluble receptor decoy inhibitor. Antimicrob. Agents Chemother. 53:1210–12 [Google Scholar]
  232. Shatalin K, Gusarov I, Avetissova E, Shatalina Y, McQuade LE. 232.  et al. 2008. Bacillus anthracis-derived nitric oxide is essential for pathogen virulence and survival in macrophages. PNAS 105:1009–13 [Google Scholar]
  233. Shen Y, Guo Q, Zhukovskaya NL, Drum CL, Bohm A, Tang WJ. 233.  2004. Structure of anthrax edema factor–calmodulin–adenosine 5′-(α,β-methylene)-triphosphate complex reveals an alternative mode of ATP binding to the catalytic site. Biochem. Biophys. Res. Commun. 317:309–14 [Google Scholar]
  234. Shen Y, Lee YS, Soelaiman S, Bergson P, Lu D. 234.  et al. 2002. Physiological calcium concentrations regulate calmodulin binding and catalysis of adenylyl cyclase exotoxins. EMBO J. 21:6721–32 [Google Scholar]
  235. Shen Y, Zhukovskaya NL, Zimmer MI, Soelaiman S, Bergson P. 235.  et al. 2004. Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection. PNAS 101:3242–47 [Google Scholar]
  236. Sherer K, Li Y, Cui X, Li X, Subramanian M. 236.  et al. 2007. Fluid support worsens outcome and negates the benefit of protective antigen-directed monoclonal antibody in a lethal toxin-infused rat Bacillus anthracis shock model. Crit. Care Med. 35:1560–67 [Google Scholar]
  237. Shoop WL, Xiong Y, Wiltsie J, Woods A, Guo J. 237.  et al. 2005. Anthrax lethal factor inhibition. PNAS 102:7958–63 [Google Scholar]
  238. Singh Y, Klimpel KR, Arora N, Sharma M, Leppla SH. 238.  1994. The chymotrypsin-sensitive site, FFD315, in anthrax toxin protective antigen is required for translocation of lethal factor. J. Biol. Chem. 269:29039–46 [Google Scholar]
  239. Sirard JC, Mock M, Fouet A. 239.  1994. The three Bacillus anthracis toxin genes are coordinately regulated by bicarbonate and temperature. J. Bacteriol. 176:5188–92 [Google Scholar]
  240. Smith H. 240.  2000. Discovery of the anthrax toxin: the beginning of in vivo studies on pathogenic bacteria. Trends Microbiol. 8:199–200 [Google Scholar]
  241. Smith H, Keppie J. 241.  1962. The terminal phase of anthrax. Br. J. Exp. Pathol. 43:684–86 [Google Scholar]
  242. Smith H, Keppie J, Ross JM, Stanley JL. 242.  1954. Observations on the cause of death in experimental anthrax. Lancet 267:474–76 [Google Scholar]
  243. Solano-Collado V, Lurz R, Espinosa M, Bravo A. 243.  2013. The pneumococcal MgaSpn virulence transcriptional regulator generates multimeric complexes on linear double-stranded DNA. Nucleic Acids Res. 41:6975–91 [Google Scholar]
  244. Sun C, Fang H, Xie T, Auth RD, Patel N. 244.  et al. 2012. Anthrax lethal toxin disrupts intestinal barrier function and causes systemic infections with enteric bacteria. PLOS ONE 7:e33583 [Google Scholar]
  245. Szarowicz SE, During RL, Li W, Quinn CP, Tang WJ, Southwick FS. 245.  2009. Bacillus anthracis edema toxin impairs neutrophil actin-based motility. Infect. Immun. 77:2455–64 [Google Scholar]
  246. Terra JK, Cote CK, France B, Jenkins AL, Bozue JA. 246.  et al. 2010. Cutting edge: resistance to Bacillus anthracis infection mediated by a lethal toxin sensitive allele of Nalp1b/Nlrp1b. J. Immunol. 184:17–20 [Google Scholar]
  247. Thomas D, Naughton J, Cote C, Welkos S, Manchester M, Young JA. 247.  2012. Delayed toxicity associated with soluble anthrax toxin receptor decoy-Ig fusion protein treatment. PLOS ONE 7:e34611 [Google Scholar]
  248. Tinsley E, Naqvi A, Bourgogne A, Koehler TM, Khan SA. 248.  2004. Isolation of a minireplicon of the virulence plasmid pXO2 of Bacillus anthracis and characterization of the plasmid-encoded RepS replication protein. J. Bacteriol. 186:2717–23 [Google Scholar]
  249. Tournier JN, Quesnel-Hellmann A, Mathieu J, Montecucco C, Tang WJ. 249.  et al. 2005. Anthrax edema toxin cooperates with lethal toxin to impair cytokine secretion during infection of dendritic cells. J. Immunol. 174:4934–41 [Google Scholar]
  250. Tournier JN, Rossi PS, Quesnel-Hellmann A, Baldari CT. 250.  2009. Anthrax toxins: a weapon to systematically dismantle the host immune defenses. Mol. Aspects Med. 30:456–66 [Google Scholar]
  251. Tsvetanova B, Wilson AC, Bongiorni C, Chiang C, Hoch JA, Perego M. 251.  2007. Opposing effects of histidine phosphorylation regulate the AtxA virulence transcription factor in Bacillus anthracis. Mol. Microbiol. 63:644–55 [Google Scholar]
  252. Turnbull PC, Broster MG, Carman JA, Manchee RJ, Melling J. 252.  1986. Development of antibodies to protective antigen and lethal factor components of anthrax toxin in humans and guinea pigs and their relevance to protective immunity. Infect. Immun. 52:356–63 [Google Scholar]
  253. Uchida I, Hornung JM, Thorne CB, Klimpel KR, Leppla SH. 253.  1993. Cloning and characterization of a gene whose product is a trans-activator of anthrax toxin synthesis. J. Bacteriol. 175:5329–38 [Google Scholar]
  254. Uchida I, Makino S, Sekizaki T, Terakado N. 254.  1997. Cross-talk to the genes for Bacillus anthracis capsule synthesis by atxA, the gene encoding the trans-activator of anthrax toxin synthesis. Mol. Microbiol. 23:1229–40 [Google Scholar]
  255. Uchida M, Harada T, Enkhtuya J, Kusumoto A, Kobayashi Y. 255.  et al. 2012. Protective effect of Bacillus anthracis surface protein EA1 against anthrax in mice. Biochem. Biophys. Res. Commun. 421:323–28 [Google Scholar]
  256. Ulmer TS, Soelaiman S, Li S, Klee CB, Tang WJ, Bax A. 256.  2003. Calcium dependence of the interaction between calmodulin and anthrax edema factor. J. Biol. Chem. 278:29261–66 [Google Scholar]
  257. Van Ert MN, Easterday WR, Huynh LY, Okinaka RT, Hugh-Jones ME. 257.  et al. 2007. Global genetic population structure of Bacillus anthracis. PLOS ONE 2:e461 [Google Scholar]
  258. van Sorge NM, Ebrahimi CM, McGillivray SM, Quach D, Sabet M. 258.  et al. 2008. Anthrax toxins inhibit neutrophil signaling pathways in brain endothelium and contribute to the pathogenesis of meningitis. PLOS ONE 3e2964
  259. Vitale G, Bernardi L, Napolitani G, Mock M, Montecucco C. 259.  2000. Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochem. J. 352:Pt 3739–45 [Google Scholar]
  260. Vitale G, Pellizzari R, Recchi C, Napolitani G, Mock M, Montecucco C. 260.  1998. Anthrax lethal factor cleaves the N-terminus of MAPKKs and induces tyrosine/threonine phosphorylation of MAPKs in cultured macrophages. Biochem. Biophys. Res. Commun. 248:706–11 [Google Scholar]
  261. von Moltke J, Trinidad NJ, Moayeri M, Kintzer AF, Wang SB. 261.  et al. 2012. Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature 490:107–11 [Google Scholar]
  262. Walker JS, Lincoln RE, Klein F. 262.  1967. Pathophysiological and biochemical changes in anthrax. Fed. Proc. 26:1539–44 [Google Scholar]
  263. Warfel JM, D'Agnillo F. 263.  2011. Anthrax lethal toxin-mediated disruption of endothelial VE-cadherin is attenuated by inhibition of the Rho-associated kinase pathway. Toxins 3:1278–93 [Google Scholar]
  264. Warfel JM, Steele AD, D'Agnillo F. 264.  2005. Anthrax lethal toxin induces endothelial barrier dysfunction. Am. J. Pathol. 166:1871–81 [Google Scholar]
  265. Watson LE, Kuo SR, Katki K, Dang T, Park SK. 265.  et al. 2007. Anthrax toxins induce shock in rats by depressed cardiac ventricular function. PLOS ONE 2:e466 [Google Scholar]
  266. Webster JI, Sternberg EM. 266.  2005. Anthrax lethal toxin represses glucocorticoid receptor (GR) transactivation by inhibiting GR-DNA binding in vivo. Mol. Cell Endocrinol. 241:21–31 [Google Scholar]
  267. Webster JI, Tonelli LH, Moayeri M, Simons SS Jr, Leppla SH, Sternberg EM. 267.  2003. Anthrax lethal factor represses glucocorticoid and progesterone receptor activity. PNAS 100:5706–11 [Google Scholar]
  268. Wein AN, Williams B, Liu S, Ermolinsky B, Provenzano D. 268.  et al. 2012. Small molecule inhibitors of Bacillus anthracis protective antigen proteolytic activation and oligomerization. J. Med. Chem. 55:7998–8006 [Google Scholar]
  269. Weiner ZP, Ernst SM, Boyer AE, Gallegos-Candela M, Barr JR, Glomski IJ. 269.  2013. Circulating lethal toxin decreases the ability of neutrophils to respond to Bacillus anthracis. Cell. Microbiol. 16:504–18 [Google Scholar]
  270. Weiss S, Kobiler D, Levy H, Marcus H, Pass A. 270.  et al. 2006. Immunological correlates for protection against intranasal challenge of Bacillus anthracis spores conferred by a protective antigen-based vaccine in rabbits. Infect. Immun. 74:394–98 [Google Scholar]
  271. Welkos S, Friedlander A, Weeks S, Little S, Mendelson I. 271.  2002. In-vitro characterisation of the phagocytosis and fate of anthrax spores in macrophages and the effects of anti-PA antibody. J. Med. Microbiol. 51:821–31 [Google Scholar]
  272. Wickliffe KE, Leppla SH, Moayeri M. 272.  2008. Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome. Cell. Microbiol. 10:332–43 [Google Scholar]
  273. Wigelsworth DJ, Krantz BA, Christensen KA, Lacy DB, Juris SJ, Collier RJ. 273.  2004. Binding stoichiometry and kinetics of the interaction of a human anthrax toxin receptor, CMG2, with protective antigen. J. Biol. Chem. 279:23349–56 [Google Scholar]
  274. Wright GG, Mandell GL. 274.  1986. Anthrax toxin blocks priming of neutrophils by lipopolysaccharide and by muramyl dipeptide. J. Exp. Med. 164:1700–9 [Google Scholar]
  275. Wright JG, Plikaytis BD, Rose CE, Parker SD, Babcock J. 275.  et al. 2014. Effect of reduced dose schedules and intramuscular injection of anthrax vaccine adsorbed on immunological response and safety profile: a randomized trial. Vaccine 32:1019–28 [Google Scholar]
  276. Xu L, Fang H, Frucht DM. 276.  2008. Anthrax lethal toxin increases superoxide production in murine neutrophils via differential effects on MAPK signaling pathways. J. Immunol. 180:4139–47 [Google Scholar]
  277. Yan M, Roehrl MH, Basar E, Wang JY. 277.  2007. Selection and evaluation of the immunogenicity of protective antigen mutants as anthrax vaccine candidates. Vaccine 26:947–55 [Google Scholar]
  278. Yang J, Woo SS, Ryu YH, Yun CH, Cho MH. 278.  et al. 2009. Bacillus anthracis lethal toxin attenuates lipoteichoic acid-induced maturation and activation of dendritic cells through a unique mechanism. Mol. Immunol. 46:3261–68 [Google Scholar]
  279. Yeager LA, Chopra AK, Peterson JW. 279.  2009. Bacillus anthracis edema toxin suppresses human macrophage phagocytosis and cytoskeletal remodeling via the protein kinase A and exchange protein activated by cyclic AMP pathways. Infect. Immun. 77:2530–43 [Google Scholar]
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