Anthrax toxin protective antigen protein (PA, 83 kDa) binds to receptors on the surface of mammalian cells, is cleaved by the cell surface protease furin, and then captures either of the two other toxin proteins, lethal factor (LF, 90 kDa) or edema factor (EF, 89 kDa). The PA-LF and PA-EF complexes enter cells by endocytosis via lipid rafts and pass through several endocytic vesicle populations, finally allowing LF and EF escape to the cytosol. EF is a calcium- and calmodulin-dependent adenylyl cyclase that causes large and unregulated increases in intracellular cAMP concentrations. LF is a metalloprotease that cleaves several mitogen-activated protein kinase kinases (MEKs). Collaborative studies have examined the interaction of LF with peptide substrates and clarified structural details of the catalytic mechanism. Inhibitors of furin and of the LF protease activity were shown to be effective in protecting cells and, in some cases, animals from toxin action. To understand how the toxin contributes to pathogenesis in animals, we extended to rats the prior studies in mice, and showed that LF causes a circulatory shock response, but one that clearly differs from that induced by gram-negative bacteria and endotoxin. Comparisons among inbred mouse strains showed that the sensitivity of mouse macrophages from certain strains to LF cannot explain the large differences in susceptibility of mice to the toxin. In studies of Bacillus anthracis, we compared regulation of gene expression in the B. anthracis to that in Bacillus cereus to explain why these bacteria differ in hemolytic phenotype. The PlcR regulon in B. anthracis was shown to lack several components present in B. cereus. A novel fusion of the PlcR and PapR proteins was shown to constitute an active transcriptional regulator able to bind to the specific PlcR DNA target sequence. Collaborative efforts related to anthrax vaccine development included studies that mapped an epitope in the receptor binding region of PA that is recognized by a neutralizing monoclonal antibody. Antibodies of higher affinity to this epitope were obtained by phage display of randomly mutated antibody libraries. A conjugate of polyglutamate to PA was shown to induce antibodies to both PA and to the bacterial capsular material, so that both anti-toxin and anti-bacterial antibodies were provided by a single immunogen. Knowledge of anthrax toxin structure and function was used to design cytotoxins specific for cancer cells. Specifically, we created diphtheria-toxin fusion proteins dependent on cell-surface plasminogen activator.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Niaid Extramural Activities
United States
Zip Code
Okugawa, Shu; Moayeri, Mahtab; Pomerantsev, Andrei P et al. (2012) Lipoprotein biosynthesis by prolipoprotein diacylglyceryl transferase is required for efficient spore germination and full virulence of Bacillus anthracis. Mol Microbiol 83:96-109
Chen, Zhaochun; Moayeri, Mahtab; Zhao, Huaying et al. (2009) Potent neutralization of anthrax edema toxin by a humanized monoclonal antibody that competes with calmodulin for edema factor binding. Proc Natl Acad Sci U S A 106:13487-92
Chen, Zhaochun; Moayeri, Mahtab; Crown, Devorah et al. (2009) Novel chimpanzee/human monoclonal antibodies that neutralize anthrax lethal factor, and evidence for possible synergy with anti-protective antigen antibody. Infect Immun 77:3902-8
Pomerantsev, Andrei P; Pomerantseva, Olga M; Camp, Andrew S et al. (2009) PapR peptide maturation: role of the NprB protease in Bacillus cereus 569 PlcR/PapR global gene regulation. FEMS Immunol Med Microbiol 55:361-77
Wickliffe, Katherine E; Leppla, Stephen H; Moayeri, Mahtab (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
Levin, Tera C; Wickliffe, Katherine E; Leppla, Stephen H et al. (2008) Heat shock inhibits caspase-1 activity while also preventing its inflammasome-mediated activation by anthrax lethal toxin. Cell Microbiol :
Wickliffe, Katherine E; Leppla, Stephen H; Moayeri, Mahtab (2008) Killing of macrophages by anthrax lethal toxin: involvement of the N-end rule pathway. Cell Microbiol 10:1352-62
Gupta, Pradeep K; Liu, Shihui; Batavia, Mariska P et al. (2008) The diphthamide modification on elongation factor-2 renders mammalian cells resistant to ricin. Cell Microbiol 10:1687-94
Shivachandra, Sathish B; Li, Qin; Peachman, Kristina K et al. (2007) Multicomponent anthrax toxin display and delivery using bacteriophage T4. Vaccine 25:1225-35
Watson, Linley E; Mock, Jonathan; Lal, Hind et al. (2007) Lethal and edema toxins of anthrax induce distinct hemodynamic dysfunction. Front Biosci 12:4670-5

Showing the most recent 10 out of 81 publications