Bacillus anthracis secretes exotoxins which act through several mechanisms including those that can subvert adaptive immunity with respect both to antigen presenting cell and T cell function. The combination of Protective Antigen (PA) and Lethal Factor (LF) forming Lethal Toxin (LT), acts within host cells to down-regulate the mitogen activated protein kinase (MAPK) signaling cascade. Until recently the MAPK kinases were the only known substrate for LT; over the past few years it has become evident that LT also cleaves Nlrp1, leading to inflammasome activation and macrophage death. The predicted downstream consequences of subverting these important cellular pathways are impaired antigen presentation and adaptive immunity. In contrast to this, recent work has indicated that robust memory T cell responses to B. anthracis antigens can be identified following natural anthrax infection. We discuss how LT affects the adaptive immune response and specifically the identification of B. anthracis epitopes that are both immunogenic and protective with the potential for inclusion in protein sub-unit based vaccines.
References
[1]
Baillie, L.W. Past, imminent and future human medical countermeasures for anthrax. J. Appl. Microbiol. 2006, 101, 594–606, doi:10.1111/j.1365-2672.2006.03112.x.
[2]
Shlyakhov, E.N.; Rubinstein, E. Human live anthrax vaccine in the former USSR. Vaccine 1994, 12, 727–730, doi:10.1016/0264-410X(94)90223-2.
[3]
Baillie, L.W.; Fowler, K.; Turnbull, P.C. Human immune responses to the UK human anthrax vaccine. J. Appl. Microbiol. 1999, 87, 306–308, doi:10.1046/j.1365-2672.1999.00899.x.
Shlyakhov, E.; Rubinstein, E.; Novikov, I. Anthrax post-vaccinal cell-mediated immunity in humans: Kinetics pattern. Vaccine 1997, 15, 631–636, doi:10.1016/S0264-410X(96)00286-1.
[6]
Splino, M.; Patocka, J.; Prymula, R.; Chlibek, R. Anthrax vaccines. Ann. Saudi. Med. 2005, 25, 143–149.
[7]
Leppla, S.H.; Robbins, J.B.; Schneerson, R.; Shiloach, J. Development of an improved vaccine for anthrax. J. Clin. Invest. 2002, 110, 141–144.
[8]
Brey, R.N. Molecular basis for improved anthrax vaccines. Adv. Drug Deliv. Rev. 2005, 57, 1266–1292, doi:10.1016/j.addr.2005.01.028.
[9]
Baillie, L. The development of new vaccines against Bacillus anthracis. J. Appl. Microbiol. 2001, 91, 609–613, doi:10.1046/j.1365-2672.2001.01498.x.
[10]
Enstone, J.E.; Wale, M.C.; Nguyen-Van-Tam, J.S.; Pearson, J.C. Adverse medical events in British service personnel following anthrax vaccination. Vaccine 2003, 21, 1348–1354, doi:10.1016/S0264-410X(02)00690-4.
[11]
Brown, B.K.; Cox, J.; Gillis, A.; VanCott, T.C.; Marovich, M.; Milazzo, M.; Antonille, T.S.; Wieczorek, L.; McKee, K.T., Jr.; Metcalfe, K.; et al. Phase I study of safety and immunogenicity of an Escherichia coli-derived recombinant protective antigen (rPA) vaccine to prevent anthrax in adults. PLoS One 2010, 5, e13849.
[12]
Campbell, J.D.; Clement, K.H.; Wasserman, S.S.; Donegan, S.; Chrisley, L.; Kotloff, K.L. Safety, reactogenicity and immunogenicity of a recombinant protective antigen anthrax vaccine given to healthy adults. Hum. Vaccin. 2007, 3, 205–211, doi:10.4161/hv.3.5.4459.
[13]
Gorse, G.J.; Keitel, W.; Keyserling, H.; Taylor, D.N.; Lock, M.; Alves, K.; Kenner, J.; Deans, L.; Gurwith, M. Immunogenicity and tolerance of ascending doses of a recombinant protective antigen (rPA102) anthrax vaccine: A randomized, double-blinded, controlled, multicenter trial. Vaccine 2006, 24, 5950–5959.
[14]
Williamson, E.D.; Hodgson, I.; Walker, N.J.; Topping, A.W.; Duchars, M.G.; Mott, J.M.; Estep, J.; Lebutt, C.; Flick-Smith, H.C.; Jones, H.E.; et al. Immunogenicity of recombinant protective antigen and efficacy against aerosol challenge with anthrax. Infect. Immun. 2005, 73, 5978–5987, doi:10.1128/IAI.73.9.5978-5987.2005.
[15]
Garmory, H.S.; Titball, R.W.; Griffin, K.F.; Hahn, U.; Bohm, R.; Beyer, W. Salmonella enterica serovar typhimurium expressing a chromosomally integrated copy of the Bacillus anthracis protective antigen gene protects mice against an anthrax spore challenge. Infect. Immun. 2003, 71, 3831–3836, doi:10.1128/IAI.71.7.3831-3836.2003.
[16]
Langley, W.A.; Bradley, K.C.; Li, Z.N.; Smith, M.E.; Schnell, M.J.; Steinhauer, D.A. Induction of neutralizing antibody responses to anthrax protective antigen by using influenza virus vectors: Implications for disparate immune system priming pathways. J. Virol. 2010, 84, 8300–8307, doi:10.1128/JVI.00183-10.
[17]
Galloway, D.R.; Baillie, L. DNA vaccines against anthrax. Expert. Opin. Biol. Ther. 2004, 4, 1661–1667, doi:10.1517/14712598.4.10.1661.
[18]
Phipps, A.J.; Premanandan, C.; Barnewall, R.E.; Lairmore, M.D. Rabbit and nonhuman primate models of toxin-targeting human anthrax vaccines. Microbiol. Mol. Biol. Rev. 2004, 68, 617–629, doi:10.1128/MMBR.68.4.617-629.2004.
[19]
Beedham, R.J.; Turnbull, P.C.; Williamson, E.D. Passive transfer of protection against Bacillus anthracis infection in a murine model. Vaccine 2001, 19, 4409–4416, doi:10.1016/S0264-410X(01)00197-9.
[20]
Staats, H.F.; Alam, S.M.; Scearce, R.M.; Kirwan, S.M.; Zhang, J.X.; Gwinn, W.M.; Haynes, B.F. In vitro and in vivo characterization of anthrax anti-protective antigen and anti-lethal factor monoclonal antibodies after passive transfer in a mouse lethal toxin challenge model to define correlates of immunity. Infect. Immun. 2007, 75, 5443–5452, doi:10.1128/IAI.00529-07.
[21]
Pitt, M.L.; Little, S.F.; Ivins, B.E.; Fellows, P.; Barth, J.; Hewetson, J.; Gibbs, P.; Dertzbaugh, M.; Friedlander, A.M. In vitro correlate of immunity in a rabbit model of inhalational anthrax. Vaccine 2001, 19, 4768–4773, doi:10.1016/S0264-410X(01)00234-1.
[22]
Little, S.F.; Webster, W.M.; Ivins, B.E.; Fellows, P.F.; Norris, S.L.; Andrews, G.P. Development of an in vitro-based potency assay for anthrax vaccine. Vaccine 2004, 22, 2843–2852, doi:10.1016/j.vaccine.2003.12.027.
[23]
Little, S.F.; Ivins, B.E.; Fellows, P.F.; Friedlander, A.M. Passive protection by polyclonal antibodies against Bacillus anthracis infection in guinea pigs. Infect.Immun. 1997, 65, 5171–5175.
[24]
McBride, B.W.; Mogg, A.; Telfer, J.L.; Lever, M.S.; Miller, J.; Turnbull, P.C.; Baillie, L. Protective efficacy of a recombinant protective antigen against Bacillus anthracis challenge and assessment of immunological markers. Vaccine 1998, 16, 810–817, doi:10.1016/S0264-410X(97)00268-5.
[25]
Reuveny, S.; White, M.D.; Adar, Y.Y.; Kafri, Y.; Altboum, Z.; Gozes, Y.; Kobiler, D.; Shafferman, A.; Velan, B. Search for correlates of protective immunity conferred by anthrax vaccine. Infect. Immun. 2001, 69, 2888–2893, doi:10.1128/IAI.69.5.2888-2893.2001.
[26]
Weiss, S.; Kobiler, D.; Levy, H.; Marcus, H.; Pass, A.; Rothschild, N.; Altboum, Z. Immunological correlates for protection against intranasal challenge of Bacillus anthracis spores conferred by a protective antigen-based vaccine in rabbits. Infect. Immun. 2006, 74, 394–398, doi:10.1128/IAI.74.1.394-398.2006.
[27]
Pitt, M.L.; Little, S.; Ivins, B.E.; Fellows, P.; Boles, J.; Barth, J.; Hewetson, J.; Friedlander, A.M. In vitro correlate of immunity in an animal model of inhalational anthrax. J. Appl. Microbiol. 1999, 87, 304.
[28]
Fellows, P.F.; Linscott, M.K.; Ivins, B.E.; Pitt, M.L.; Rossi, C.A.; Gibbs, P.H.; Friedlander, A.M. Efficacy of a human anthrax vaccine in guinea pigs, rabbits, and rhesus macaques against challenge by Bacillus anthracis isolates of diverse geographical origin. Vaccine 2001, 19, 3241–3247, doi:10.1016/S0264-410X(01)00021-4.
[29]
Turnbull, P.C.; Broster, M.G.; Carman, J.A.; Manchee, R.J.; Melling, J. 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. 1986, 52, 356–363.
[30]
Baillie, L.W.; Huwar, T.B.; Moore, S.; Mellado-Sanchez, G.; Rodriguez, L.; Neeson, B.N.; Flick-Smith, H.C.; Jenner, D.C.; Atkins, H.S.; Ingram, R.J.; et al. An anthrax subunit vaccine candidate based on protective regions of Bacillus anthracis protective antigen and lethal factor. Vaccine 2010, 28, 6740–6748.
[31]
Turnbull, P.C.; Leppla, S.H.; Broster, M.G.; Quinn, C.P.; Melling, J. Antibodies to anthrax toxin in humans and guinea pigs and their relevance to protective immunity. Med. Microbiol. Immunol. 1988, 177, 293–303.
[32]
Van den Enden, E.; Van Gompel, A.; Van Esbroeck, M. Cutaneous anthrax, Belgian traveler. Emerg. Infect. Dis. 2006, 12, 523–525, doi:10.3201/eid1203.051407.
[33]
Brenneman, K.E.; Doganay, M.; Akmal, A.; Goldman, S.; Galloway, D.R.; Mateczun, A.J.; Cross, A.S.; Baillie, L.W. The early humoral immune response to Bacillus anthracis toxins in patients infected with cutaneous anthrax. FEMS Immunol. Med. Microbiol. 2011, 62, 164–172, doi:10.1111/j.1574-695X.2011.00800.x.
[34]
Little, S.F.; Ivins, B.E.; Webster, W.M.; Fellows, P.F.; Pitt, M.L.; Norris, S.L.; Andrews, G.P. Duration of protection of rabbits after vaccination with Bacillus anthracis recombinant protective antigen vaccine. Vaccine 2006, 24, 2530–2536.
[35]
Crowe, S.R.; Ash, L.L.; Engler, R.J.; Ballard, J.D.; Harley, J.B.; Farris, A.D.; James, J.A. Select human anthrax protective antigen epitope-specific antibodies provide protection from lethal toxin challenge. J. Infect. Dis. 2010, 202, 251–260, doi:10.1086/653495.
[36]
Crowe, S.R.; Garman, L.; Engler, R.J.; Farris, A.D.; Ballard, J.D.; Harley, J.B.; James, J.A. Anthrax vaccination induced anti-lethal factor IgG: Fine specificity and neutralizing capacity. Vaccine 2011, 29, 3670–3678, doi:10.1016/j.vaccine.2011.03.011.
[37]
Smith, K.; Crowe, S.R.; Garman, L.; Guthridge, C.J.; Muther, J.J.; McKee, E.; Zheng, N.Y.; Farris, A.D.; Guthridge, J.M.; Wilson, P.C.; et al. Human monoclonal antibodies generated following vaccination with AVA provide neutralization by blocking furin cleavage but not by preventing oligomerization. Vaccine 2012, 30, 4276–4283, doi:10.1016/j.vaccine.2012.03.002.
[38]
Hewetson, J.F.; Little, S.F.; Ivins, B.E.; Johnson, W.M.; Pittman, P.R.; Brown, J.E.; Norris, S.L.; Nielsen, C.J. An in vivo passive protection assay for the evaluation of immunity in AVA-vaccinated individuals. Vaccine 2008, 26, 4262–4266, doi:10.1016/j.vaccine.2008.05.068.
[39]
Lim, N.K.; Kim, J.H.; Oh, M.S.; Lee, S.; Kim, S.Y.; Kim, K.S.; Kang, H.J.; Hong, H.J.; Inn, K.S. An anthrax lethal factor-neutralizing monoclonal antibody protects rats before and after challenge with anthrax toxin. Infect. Immun. 2005, 73, 6547–6551.
[40]
Nguyen, M.L.; Terzyan, S.; Ballard, J.D.; James, J.A.; Farris, A.D. The major neutralizing antibody responses to recombinant anthrax lethal and edema factors are directed to non-cross-reactive epitopes. Infect. Immun. 2009, 77, 4714–4723.
Price, B.M.; Liner, A.L.; Park, S.; Leppla, S.H.; Mateczun, A.; Galloway, D.R. Protection against anthrax lethal toxin challenge by genetic immunization with a plasmid encoding the lethal factor protein. Infect. Immun. 2001, 69, 4509–4515, doi:10.1128/IAI.69.7.4509-4515.2001.
[43]
Pezard, C.; Weber, M.; Sirard, J.C.; Berche, P.; Mock, M. Protective immunity induced by Bacillus anthracis toxin-deficient strains. Infect. Immun. 1995, 63, 1369–1372.
[44]
Hermanson, G.; Whitlow, V.; Parker, S.; Tonsky, K.; Rusalov, D.; Ferrari, M.; Lalor, P.; Komai, M.; Mere, R.; Bell, M.; et al. A cationic lipid-formulated plasmid DNA vaccine confers sustained antibody-mediated protection against aerosolized anthrax spores. Proc. Natl. Acad. Sci. USA 2004, 101, 13601–13606.
[45]
Kwok, W.W.; Tan, V.; Gillette, L.; Littell, C.T.; Soltis, M.A.; LaFond, R.B.; Yang, J.; James, E.A.; DeLong, J.H. Frequency of epitope-specific naive CD4(+) T cells correlates with immunodominance in the human memory repertoire. J. Immunol. 2012, 188, 2537–2544, doi:10.4049/jimmunol.1102190.
[46]
Kwok, W.W.; Yang, J.; James, E.; Bui, J.; Huston, L.; Wiesen, A.R.; Roti, M. The anthrax vaccine adsorbed vaccine generates protective antigen (PA)-Specific CD4+ T cells with a phenotype distinct from that of naive PA T cells. Infect. Immun. 2008, 76, 4538–4545, doi:10.1128/IAI.00324-08.
[47]
Laughlin, E.M.; Miller, J.D.; James, E.; Fillos, D.; Ibegbu, C.C.; Mittler, R.S.; Akondy, R.; Kwok, W.; Ahmed, R.; Nepom, G. Antigen-specific CD4+ T cells recognize epitopes of protective antigen following vaccination with an anthrax vaccine. Infect. Immun. 2007, 75, 1852–1860, doi:10.1128/IAI.01814-06.
[48]
Glomski, I.J.; Corre, J.P.; Mock, M.; Goossens, P.L. Cutting Edge: IFN-gamma-producing CD4 T lymphocytes mediate spore-induced immunity to capsulated Bacillus anthracis. J. Immunol. 2007, 178, 2646–2650.
[49]
Ingram, R.J.; Metan, G.; Maillere, B.; Doganay, M.; Ozkul, Y.; Kim, L.U.; Baillie, L.; Dyson, H.; Williamson, E.D.; Chu, K.K.; et al. Natural exposure to cutaneous anthrax gives long-lasting T cell immunity encompassing infection-specific epitopes. J. Immunol. 2010, 184, 3814–3821.
[50]
Wattiau, P.; Govaerts, M.; Frangoulidis, D.; Fretin, D.; Kissling, E.; Van, H.M.; China, B.; Poncin, M.; Pirenne, Y.; Hanquet, G. Immunologic response of unvaccinated workers exposed to anthrax, Belgium. Emerg. Infect. Dis. 2009, 15, 1637–1640, doi:10.3201/eid1510.081717.
[51]
Doolan, D.L.; Freilich, D.A.; Brice, G.T.; Burgess, T.H.; Berzins, M.P.; Bull, R.L.; Graber, N.L.; Dabbs, J.L.; Shatney, L.L.; Blazes, D.L.; et al. The US capitol bioterrorism anthrax exposures: Clinical epidemiological and immunological characteristics. J. Infect. Dis. 2007, 195, 174–184, doi:10.1086/510312.
Scobie, H.M.; Rainey, G.J.; Bradley, K.A.; Young, J.A. Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor. Proc. Natl. Acad. Sci. USA 2003, 100, 5170–5174.
[55]
Bradley, K.A.; Mogridge, J.; Mourez, M.; Collier, R.J.; Young, J.A. Identification of the cellular receptor for anthrax toxin. Nature 2001, 414, 225–229, doi:10.1038/n35101999.
Bradley, K.A.; Mogridge, J.; Jonah, G.; Rainey, A.; Batty, S.; Young, J.A. Binding of anthrax toxin to its receptor is similar to alpha integrin-ligand interactions. J. Biol. Chem. 2003, 278, 49342–49347.
Martchenko, M.; Jeong, S.Y.; Cohen, S.N. Heterodimeric integrin complexes containing beta1-integrin promote internalization and lethality of anthrax toxin. Proc. Natl. Acad. Sci. USA 2010, 107, 15583–15588.
[60]
Scobie, H.M.; Thomas, D.; Marlett, J.M.; Destito, G.; Wigelsworth, D.J.; Collier, R.J.; Young, J.A.; Manchester, M. A soluble receptor decoy protects rats against anthrax lethal toxin challenge. J. Infect. Dis. 2005, 192, 1047–1051, doi:10.1086/432731.
[61]
Liu, S.; Crown, D.; Miller-Randolph, S.; Moayeri, M.; Wang, H.; Hu, H.; Morley, T.; Leppla, S.H. Capillary morphogenesis protein-2 is the major receptor mediating lethality of anthrax toxin in vivo. Proc. Natl. Acad. Sci. USA 2009, 106, 12424–12429.
[62]
Hu, H.; Leppla, S.H. Anthrax toxin uptake by primary immune cells as determined with a lethal factor-beta-lactamase fusion protein. PLoS One 2009, 4, e7946, doi:10.1371/journal.pone.0007946.
[63]
Pannifer, A.D.; Wong, T.Y.; Schwarzenbacher, R.; Renatus, M.; Petosa, C.; Bienkowska, J.; Lacy, D.B.; Collier, R.J.; Park, S.; Leppla, S.H.; Hanna, P.; Liddington, R.C. Crystal structure of the anthrax lethal factor. Nature 2001, 414, 229–233.
[64]
Duesbery, N.S.; Vande Woude, G.F. Anthrax lethal factor causes proteolytic inactivation of mitogen-activated protein kinase kinase. J. Appl. Microbiol. 1999, 87, 289–293, doi:10.1046/j.1365-2672.1999.00892.x.
[65]
Bragg, T.S.; Robertson, D.L. Nucleotide sequence and analysis of the lethal factor gene (lef) from Bacillus anthracis. Gene 1989, 81, 45–54, doi:10.1016/0378-1119(89)90335-1.
[66]
Lacy, D.B.; Mourez, M.; Fouassier, A.; Collier, R.J. Mapping the anthrax protective antigen binding site on the lethal and edema factors. J. Biol. Chem. 2002, 277, 3006–3010.
[67]
Arora, N.; Leppla, S.H. Residues-1–254 of anthrax toxin lethal factor are sufficient to cause cellular uptake of fused polypeptides. J. Biol. Chem. 1993, 268, 3334–3341.
[68]
Liao, Q.; Strong, A.J.; Liu, Y.; Liu, Y.; Meng, P.; Fu, Y.; Touzjian, N.; Shao, Y.; Zhao, Z.; Lu, Y. HIV vaccine candidates generate in vitro T cell response to putative epitopes in Chinese-origin rhesus macaques. Vaccine 2012, 30, 1601–1608, doi:10.1016/j.vaccine.2011.12.117.
[69]
Ascenzi, P.; Visca, P.; Ippolito, G.; Spallarossa, A.; Bolognesi, M.; Montecucco, C. Anthrax toxin: A tripartite lethal combination. FEBS Lett. 2002, 531, 384–388, doi:10.1016/S0014-5793(02)03609-8.
[70]
Quinn, C.P.; Singh, Y.; Klimpel, K.R.; Leppla, S.H. Functional mapping of anthrax toxin lethal factor by in-frame insertion mutagenesis. J. Biol. Chem. 1991, 266, 20124–20130.
[71]
Liang, X.D.; Young, J.J.; Boone, S.A.; Waugh, D.S.; Duesbery, N.S. Involvement of domain II in toxicity of anthrax lethal factor. J. Biol. Chem. 2004, 279, 52473–52478.
[72]
Klimpel, K.R.; Arora, N.; Leppla, S.H. Anthrax toxin lethal factor contains a zinc metalloprotease consensus sequence which is required for lethal toxin activity. Mol. Microbiol. 1994, 13, 1093–1100, doi:10.1111/j.1365-2958.1994.tb00500.x.
Tonello, F.; Naletto, L.; Romanello, V.; Dal, M.F.; Montecucco, C. Tyrosine-728 and glutamic acid-735 are essential for the metalloproteolytic activity of the lethal factor of Bacillus anthracis. Biochem. Biophys. Res. Commun. 2004, 313, 496–502, doi:10.1016/j.bbrc.2003.11.134.
[75]
Rossetto, O.; Caccin, P.; Rigoni, M.; Tonello, F.; Bortoletto, N.; Stevens, R.C.; Montecucco, C. Active-site mutagenesis of tetanus neurotoxin implicates TYR-375 and GLU-271 in metalloproteolytic activity. Toxicon 2001, 39, 1151–1159, doi:10.1016/S0041-0101(00)00252-X.
[76]
Rigoni, M.; Caccin, P.; Johnson, E.A.; Montecucco, C.; Rossetto, O. Site-directed mutagenesis identifies active-site residues of the light chain of botulinum neurotoxin type A. Biochem. Biophys. Res. Commun. 2001, 288, 1231–1237, doi:10.1006/bbrc.2001.5911.
Lange-Carter, C.A.; Pleiman, C.M.; Gardner, A.M.; Blumer, K.J.; Johnson, G.L. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science 1993, 260, 315–319.
[80]
Hagemann, C.; Blank, J.L. The ups and downs of MEK kinase interactions. Cell Signal. 2001, 13, 863–875, doi:10.1016/S0898-6568(01)00220-0.
[81]
Gerwins, P.; Blank, J.L.; Johnson, G.L. Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway. J. Biol. Chem. 1997, 272, 8288–8295, doi:10.1074/jbc.272.13.8288.
[82]
Salmeron, A.; Ahmad, T.B.; Carlile, G.W.; Pappin, D.; Narsimhan, R.P.; Ley, S.C. Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. EMBO J. 1996, 15, 817–826.
[83]
Ichijo, H.; Nishida, E.; Irie, K.; Ten, D.P.; Saitoh, M.; Moriguchi, T.; Takagi, M.; Matsumoto, K.; Miyazono, K.; Gotoh, Y. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 1997, 275, 90–94, doi:10.1126/science.275.5296.90.
[84]
Yamaguchi, K.; Shirakabe, K.; Shibuya, H.; Irie, K.; Oishi, I.; Ueno, N.; Taniguchi, T.; Nishida, E.; Matsumoto, K. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 1995, 270, 2008–2011.
[85]
Roux, P.P.; Blenis, J. ERK and p38 MAPK-activated protein kinases: A family of protein kinases with diverse biological functions. Microbiol. Mol. Biol. Rev. 2004, 68, 320–344, doi:10.1128/MMBR.68.2.320-344.2004.
[86]
Turk, B.E. Manipulation of host signalling pathways by anthrax toxins. Biochem. J. 2007, 402, 405–417, doi:10.1042/BJ20061891.
[87]
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. 2000, 352 (Pt. 3), 739–745.
[88]
Chopra, A.P.; Boone, S.A.; Liang, X.D.; Duesbery, N.S. Anthrax lethal factor proteolysis and inactivation of MAPK kinase. J. Biol. Chem. 2003, 278, 9402–9406.
[89]
Bardwell, A.J.; Abdollahi, M.; Bardwell, L. Anthrax lethal factor-cleavage products of MAPK (mitogen-activated protein kinase) kinases exhibit reduced binding to their cognate MAPKs. Biochem. J. 2004, 378, 569–577, doi:10.1042/BJ20031382.
[90]
Seyfried, J.; Wang, X.; Kharebava, G.; Tournier, C. A novel mitogen-activated protein kinase docking site in the N terminus of MEK5alpha organizes the components of the extracellular signal-regulated kinase 5 signaling pathway. Mol. Cell Biol. 2005, 25, 9820–9828, doi:10.1128/MCB.25.22.9820-9828.2005.
[91]
Friedlander, A.M. Macrophages are sensitive to anthrax lethal toxin through an acid-dependent process. J. Biol. Chem. 1986, 261, 7123–7126.
[92]
Agrawal, A.; Lingappa, J.; Leppla, S.H.; Agrawal, S.; Jabbar, A.; Quinn, C.; Pulendran, B. Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin. Nature 2003, 424, 329–334, doi:10.1038/nature01794.
[93]
Welkos, S.L.; Friedlander, A.M. Pathogenesis and genetic control of resistance to the Sterne strain of Bacillus anthracis. Microb. Pathog. 1988, 4, 53–69, doi:10.1016/0882-4010(88)90048-4.
[94]
Welkos, S.L.; Keener, T.J.; Gibbs, P.H. Differences in susceptibility of inbred mice to Bacillus anthracis. Infect. Immun. 1986, 51, 795–800.
[95]
Jones, W.I., Jr.; Klein, F.; Walker, J.S.; Mahlandt, B.G.; Dobbs, J.P.; Lincoln, R.E. In vivo growth and distribution of anthrax bacilli in resistant, susceptible, and immunized hosts. J. Bacteriol. 1967, 94, 600–608.
[96]
Beall, F.A.; Dalldorf, F.G. The pathogenesis of the lethal effect of anthrax toxin in the rat. J. Infect. Dis. 1966, 116, 377–389, doi:10.1093/infdis/116.3.377.
[97]
Kim, S.O.; Jing, Q.; Hoebe, K.; Beutler, B.; Duesbery, N.S.; Han, J.H. Sensitizing anthrax lethal toxin-resistant macrophages to lethal toxin-induced killing by tumor necrosis factor-alpha. J. Biol. Chem. 2003, 278, 7413–7421.
[98]
Pellizzari, R.; Guidi-Rontani, C.; Vitale, G.; Mock, M.; Montecucco, C. Anthrax lethal factor cleaves MKK3 in macrophages and inhibits the LPS/IFNgamma-induced release of NO and TNFalpha. FEBS Lett. 1999, 462, 199–204, doi:10.1016/S0014-5793(99)01502-1.
[99]
Watters, J.W.; Dietrich, W.F. Genetic, physical, and transcript map of the Ltxs1 region of mouse chromosome 11. Genomics 2001, 73, 223–231.
[100]
Roberts, J.E.; Watters, J.W.; Ballard, J.D.; Dietrich, W.F. Ltx1, a mouse locus that influences the susceptibility of macrophages to cytolysis caused by intoxication with Bacillus anthracis lethal factor, maps to chromosome 11. Mol. Microbiol. 1998, 29, 581–591, doi:10.1046/j.1365-2958.1998.00953.x.
McAllister, R.D.; Singh, Y.; du Bois, W.D.; Potter, M.; Boehm, T.; Meeker, N.D.; Fillmore, P.D.; Anderson, L.M.; Poynter, M.E.; Teuscher, C. Susceptibility to anthrax lethal toxin is controlled by three linked quantitative trait loci. Am. J. Pathol. 2003, 163, 1735–1741, doi:10.1016/S0002-9440(10)63532-8.
[107]
Henry, T.; Brotcke, A.; Weiss, D.S.; Thompson, L.J.; Monack, D.M. Type I interferon signaling is required for activation of the inflammasome during Francisella infection. J. Exp. Med. 2007, 204, 987–994, doi:10.1084/jem.20062665.
[108]
Moayeri, M.; Haines, D.; Young, H.A.; Leppla, S.H. Bacillus anthracis lethal toxin induces TNF-alpha-independent hypoxia-mediated toxicity in mice. J. Clin. Invest. 2003, 112, 670–682.
[109]
Levinsohn, J.L.; Newman, Z.L.; Hellmich, K.A.; Fattah, R.; Getz, M.A.; Liu, S.; Sastalla, I.; Leppla, S.H.; Moayeri, M. Anthrax lethal factor cleavage of nlrp1 is required for activation of the inflammasome. PLoS Pathog. 2012, 8, e1002638, doi:10.1371/journal.ppat.1002638.
[110]
Newman, Z.L.; Printz, M.P.; Liu, S.; Crown, D.; Breen, L.; Miller-Randolph, S.; Flodman, P.; Leppla, S.H.; Moayeri, M. Susceptibility to anthrax lethal toxin-induced rat death is controlled by a single chromosome 10 locus that includes rNlrp1. PLoS Pathog. 2010, 6, e1000906, doi:10.1371/journal.ppat.1000906.
[111]
Newman, Z.L.; Crown, D.; Leppla, S.H.; Moayeri, M. Anthrax lethal toxin activates the inflammasome in sensitive rat macrophages. Biochem. Biophys. Res. Commun. 2010, 398, 785–789, doi:10.1016/j.bbrc.2010.07.039.
[112]
Broz, P.; von, M.J.; Jones, J.W.; Vance, R.E.; Monack, D.M. Differential requirement for Caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing. Cell Host. Microb. 2010, 8, 471–483, doi:10.1016/j.chom.2010.11.007.
[113]
Quinn, C.P.; Dull, P.M.; Semenova, V.; Li, H.; Crotty, S.; Taylor, T.H.; Steward-Clark, E.; Stamey, K.L.; Schmidt, D.S.; Stinson, K.W.; et al. Immune responses to Bacillus anthracis protective antigen in patients with bioterrorism-related cutaneous or inhalation anthrax. J. Infect. Dis. 2004, 190, 1228–1236, doi:10.1086/423937.
[114]
Ingram, R.; Ascough, S.; Kim, L.U.; Metan, G.; Doganay, M.; Baillie, L.; Williamson, E.D.; Robinson, J.H.; Maillere, B.; Sriskandan, S.; et al. Natural cutaneous anthrax infection in humans induces a long-lasting Th1, Th2, Th9 and Th17 response. 2012. to be submitted for publication.
[115]
Wickliffe, K.E.; Leppla, S.H.; Moayeri, M. Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome. Cell Microbiol. 2008, 10, 332–343.
[116]
Hanna, P.C.; Kochi, S.; Collier, R.J. Biochemical and physiological changes induced by anthrax lethal toxin in J774 macrophage-like cells. Mol. Biol. Cell 1992, 3, 1269–1277.
[117]
Paccani, S.R.; Tonello, F.; Ghittoni, R.; Natale, M.; Muraro, L.; D’Elios, M.M.; Tang, W.J.; Montecucco, C.; Baldari, C.T. Anthrax toxins suppress T lymphocyte activation by disrupting antigen receptor signaling. J. Exp. Med. 2005, 201, 325–331, doi:10.1084/jem.20041557.
[118]
Comer, J.E.; Chopra, A.K.; Peterson, J.W.; Konig, R. Direct inhibition of T-lymphocyte activation by anthrax toxins in vivo. Infect. Immun. 2005, 73, 8275–8281, doi:10.1128/IAI.73.12.8275-8281.2005.
[119]
Fang, H.; Cordoba-Rodriguez, R.; Lankford, C.S.R.; Frucht, D.M. Anthrax lethal toxin blocks MAPK kinase-dependent IL-2 production in CD4(+) T cells. J. Immun. 2005, 174, 4966–4971.
Huang, C.; Jacobson, K.; Schaller, M.D. MAP kinases and cell migration. J. Cell Sci. 2004, 117, 4619–4628, doi:10.1242/jcs.01481.
[122]
Howe, A.K. Regulation of actin-based cell migration by cAMP/PKA. Biochim. Biophys. Acta 2004, 1692, 159–174, doi:10.1016/j.bbamcr.2004.03.005.
[123]
Paccani, S.R.; Benagiano, M.; Capitani, N.; Zornetta, I.; Ladant, D.; Montecucco, C.; D’Elios, M.M.; Baldari, C.T. The adenylate cyclase toxins of bacillus anthracis and bordetella pertussis promote Th2 cell development by shaping T cell antigen receptor signaling. Plos Pathog. 2009, 5, e1000325, doi:10.1371/journal.ppat.1000325.
[124]
Boyaka, P.N.; Tafaro, A.; Fischer, R.; Leppla, S.H.; Fujihashi, K.; McGhee, J.R. Effective mucosal immunity to anthrax: Neutralizing antibodies and Th cell responses following nasal immunization with protective antigen. J. Immunol. 2003, 170, 5636–5643.
[125]
Grun, J.L.; Maurer, P.H. Different T helper cell subsets elicited in mice utilizing two different adjuvant vehicles: The role of endogenous interleukin 1 in proliferative responses. Cell Immunol. 1989, 121, 134–145, doi:10.1016/0008-8749(89)90011-7.
[126]
Marinaro, M.; Staats, H.F.; Hiroi, T.; Jackson, R.J.; Coste, M.; Boyaka, P.N.; Okahashi, N.; Yamamoto, M.; Kiyono, H.; Bluethmann, H.; Fujihashi, K.; McGhee, J.R. Mucosal adjuvant effect of cholera toxin in mice results from induction of T helper 2 (Th2) cells and IL-4. J. Immunol. 1995, 155, 4621–4629.
[127]
Yamamoto, S.; Kiyono, H.; Yamamoto, M.; Imaoka, K.; Fujihashi, K.; van Ginkel, F.W.; Noda, M.; Takeda, Y.; McGhee, J.R. A nontoxic mutant of cholera toxin elicits Th2-type responses for enhanced mucosal immunity. Proc. Natl. Acad. Sci. USA 1997, 94, 5267–5272.
[128]
Gold, J.A.; Hoshino, Y.; Hoshino, S.; Jones, M.B.; Nolan, A.; Weiden, M.D. Exogenous gamma and alpha/beta interferon rescues human macrophages from cell death induced by Bacillus anthracis. Infect. Immun. 2004, 72, 1291–1297, doi:10.1128/IAI.72.3.1291-1297.2004.
[129]
Gonzales, C.M.; Williams, C.B.; Calderon, V.E.; Huante, M.B.; Moen, S.T.; Popov, V.L.; Baze, W.B.; Peterson, J.W.; Endsley, J.J. Antibacterial role for natural killer cells in host defense to Bacillus anthracis. Infect. Immun. 2012, 80, 234–242, doi:10.1128/IAI.05439-11.
[130]
Klezovich-Benard, M.; Corre, J.P.; Jusforgues-Saklani, H.; Fiole, D.; Burjek, N.; Tournier, J.N.; Goossens, P.L. Mechanisms of NK cell-macrophage Bacillus anthracis crosstalk: A balance between stimulation by spores and differential disruption by toxins. PLoS Pathog. 2012, 8, e1002481, doi:10.1371/journal.ppat.1002481.
[131]
Devera, T.S.; Aye, L.M.; Lang, G.A.; Joshi, S.K.; Ballard, J.D.; Lang, M.L. CD1d-dependent B-cell help by NK-like T cells leads to enhanced and sustained production of Bacillus anthracis lethal toxin-neutralizing antibodies. Infect. Immun. 2010, 78, 1610–1617, doi:10.1128/IAI.00002-10.
[132]
Devera, T.S.; Joshi, S.K.; Aye, L.M.; Lang, G.A.; Ballard, J.D.; Lang, M.L. Regulation of anthrax toxin-specific antibody titers by natural killer T cell-derived IL-4 and IFNgamma. PLoS One 2011, 6, e23817.
[133]
Abboud, N.; Chow, S.K.; Saylor, C.; Janda, A.; Ravetch, J.V.; Scharff, M.D.; Casadevall, A. A requirement for FcgammaR in antibody-mediated bacterial toxin neutralization. J. Exp. Med. 2010, 207, 2395–2405, doi:10.1084/jem.20100995.
Khan, M.A.; Gallo, R.M.; Brutkiewicz, R.R. Anthrax lethal toxin impairs CD1d-mediated antigen presentation by targeting the ERK1/2 MAPK pathway. Infect. Immun. 2010, 78, 1859–1863, doi:10.1128/IAI.01307-09.
[136]
Paccani, S.R.; Benagiano, M.; Savino, M.T.; Finetti, F.; Tonello, F.; D’Elios, M.M.; Baldari, C.T. The adenylate cyclase toxin of Bacillus anthracis is a potent promoter of T(H)17 cell development. J. Allergy Clin. Immunol. 2011, 127, 1635–1637.
[137]
Allen, J.S.; Skowera, A.; Rubin, G.J.; Wessely, S.; Peakman, M. Long-lasting T cell responses to biological warfare Vaccines in human vaccinees. Clin. Infect. Dis. 2006, 43, 1–7.
[138]
Martchenko, M.; Candille, S.I.; Tang, H.; Cohen, S.N. Human genetic variation altering anthrax toxin sensitivity. Proc. Natl. Acad. Sci. USA 2012, 109, 2972–2977.
[139]
Marano, N.; Plikaytis, B.D.; Martin, S.W.; Rose, C.; Semenova, V.A.; Martin, S.K.; Freeman, A.E.; Li, H.; Mulligan, M.J.; Parker, S.D.; et al. Effects of a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on immunogenicity and safety at 7 months: A randomized trial. J. Am. Med. Assoc. 2008, 300, 1532–1543.
[140]
Ingram, R.; Baillie, L. It’s in the genes! Human genetic diversity and the response to anthrax vaccines. Expert Rev. Vaccin 2012, 11, 633–635, doi:10.1586/erv.12.41.
[141]
Fish, D.C.; Mahlandt, B.G.; Dobbs, J.P.; Lincoln, R.E. Purification and properties of in vitro-produced anthrax toxin components. J. Bacteriol. 1968, 95, 907–918.
[142]
Mock, M.; Roques, B.P. Progress in rapid screening of bacillus anthracis lethal factor activity. Proc. Natl. Acad. Sci. USA 2002, 99, 6527–6529, doi:10.1073/pnas.112220599.
