Oklahoma Medical Research Foundation (OMRF)

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Investigators
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Molecular and Immunologic Analysis of the Pathobiology of Human Anthrax

We have built and continue to advance our multidisciplinary approach to the study of the human immune response to Bacillus anthracis. We view B. anthracis as one of the most significant threats to our society as a bioterrorist agent, distinct from its use as a biological weapon. B. anthracis is alarming as a weapon of terror for several reasons: 1) the spore is long-lived, is simple to make, does not require complex and expensive equipment, and is stable in harsh environments; 2) the vaccine is of questionable efficacy, has a cumbersome injection schedule, and is not provided to civilians; 3) mortality remains high even with effective antibiotic therapy ; 4) even a small number of deaths from a rare and thus exotic disease is sufficient to cause terror in our population. Indeed, this is exactly what happened after the US Postal Service Center attacks in 2001.

The group we assembled is productive, highly interactive and has a formidable background in immunology as well as expertise in Bacillus anthracis. Our group includes faculty, fellows, technicians, veterinary staff and other support staff at four different institutions: The Oklahoma Medical Research Foundation, The University of Oklahoma, The University of Chicago, The University of Cincinnati, and Boston University. Our efforts consist of five Scientific Projects, three Technical Projects and two Core Facilities (along with Administrative and Educational cores). We attack the problem from every direction: powerful experimental models largely developed in house, a novel approach to vaccine genetics and vaccine efficacy, several host-response interactions, studies of the exotoxins, and two novel and exciting therapeutic approaches.

Specific areas of impact include the following:

How B. anthracis toxins impair the immune response to anthrax: J. Ballard Laboratory
How the human lung responds to B. anthracis spores: J. Metcalf Laboratory
How human blood cells respond to vegetative B. anthracis; K. M Coggeshall Laboratory
How the anthrax vaccine recognizes B. anthracis toxins: J. James and A.D. Farris Laboratories
How the anthrax toxins impair NK T cell responses: M. Lang Laboratory

Our efforts are on-going over seven years and we have made substantive advances. Our ultimate goal is to eliminate anthrax from the bioterrorist arsenal.

Jimmy D. Ballard, Ph.D. - How B. anthracis toxins impair the immune response to anthrax
Jordan P. Metcalf, M.D. - How the human lung responds to B. anthracis spores
K. Mark Coggeshall, Ph.D. - How human blood cells respond to vegetative B. anthracis
Judith James, M.D., Ph.D./A. Darise Farris, Ph.D. - How the anthrax vaccine recognizes B. anthracis toxins
Judith James, M.D., Ph.D./A. Darise Farris, Ph.D. - Anthrax Lethal Toxin-Induced Gene Expression Changes in Mouse Lung
Kenneth Kaufman, Ph.D. - Reverse Genomics of Anti-Protective Antigen Responses

Patrick Wilson, Ph.D. – Early Plasma Cells as a Source of Anthrax-Neutralizing Antibodies

Mark Lang, Ph.D. - Anthrax toxin-induced anergy in primary human NKT cells
Hiroyuki Matsumoto, PhD - Early protein phosphorylation triggered by anthrax toxins in human PBMCs

K. Mark Coggeshall

Iyer JK, Coggeshall KM. Cutting edge: primary innate immune cells respond efficiently to polymeric peptidoglycan, but not to peptidoglycan monomers. J Immunol 186:3841-3845, 2011. [Abstract]

Iyer JK, Khurana T, Langer M, West CM, Ballard JD, Metcalf JP, Merkel TJ, Coggeshall KM. Inflammatory cytokine response to Bacillus anthracis peptidoglycan requires phagocytosis and lysosomal trafficking. Infect Immun 78:2418-2428, 2010. [Abstract]

Peng Q, Malhotra S, Torchia JA, Kerr WG, Coggeshall KM, Humphrey MB. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.Sci Signal 3:ra38, 2010. [Abstract]

Wu W, Booth JL, Duggan ES, Wu S, Patel KB, Coggeshall KM, Metcalf JP. Innate immune response to H3N2 and H1N1 influenza virus infection in a human lung organ culture model. Virology 396:178-188, 2010. [Abstract]

Dozmorov M, Wu W, Chakrabarty K, Booth JL, Hurst RE, Coggeshall KM, Metcalf JP. Gene expression profiling of human alveolar macrophages infected by B. anthracis spores demonstrates TNF-alpha and NF-kappab are key components of the innate immune response to the pathogen. BMC Infect Dis 9:152, 2009. [Abstract]

Wu W, Mehta H, Chakrabarty K, Booth JL, Duggan ES, Patel KB, Ballard JD, Coggeshall KM, Metcalf JP. Resistance of human alveolar macrophages to Bacillus anthracis lethal toxin. J Immunol 183:5799-5806, 2009. [Abstract]

Langer M, Malykhin A, Maeda K, Chakrabarty K, Williamson KS, Feasley CL, West CM, Metcalf JP, Coggeshall KM. Bacillus anthracis peptidoglycan stimulates an inflammatory response in monocytes through the p38 mitogen-activated protein kinase pathway. PLoS One 3:e3706, 2008. [Abstract]

Chakrabarty K, Wu W, Booth JL, Duggan ES, Nagle NN, Coggeshall KM, Metcalf JP. Human lung innate immune response to Bacillus anthracis spore infection. Infect Immun 75:3729-3738, 2007. [Abstract]

Chakrabarty K, Wu W, Booth JL, Duggan ES, Coggeshall KM, Metcalf JP. Bacillus anthracis spores stimulate cytokine and chemokine innate immune responses in human alveolar macrophages through multiple mitogen-activated protein kinase pathways. Infect Immun 74:4430-4438, 2006. [Abstract]

Jordan P. Metcalf

Chakrabarty K, Wu W, Booth JL, Duggan ES, Nagle NN, Coggeshall KM, Metcalf JP. Human lung innate immune response to Bacillus anthracis spore infection. Infect Immun 75:3729-3738, 2007. [Abstract]

Jimmy D. Ballard

Bryant-Hudson KM, Shakir SM, Ballard JD. Autoregulatory characteristics of a Bacillus anthracis serine/threonine kinase. J Bacteriol 193:1833-1842, 2011. [Abstract]

Crowe SR, Garman L, Engler RJ, Farris AD, Ballard JD, Harley JB, James JA. Anthrax vaccination induced anti-lethal factor IgG: fine specificity and neutralizing capacity. Vaccine 29:3670-3678, 2011. [Abstract]

Devera TS, Joshi SK, Aye LM, Lang GA, Ballard JD, Lang ML. Regulation of anthrax toxin-specific antibody titers by natural killer T cell-derived IL-4 and IFNgamma. PLoS One 6:e23817, 2011. [Abstract]

Larabee JL, Maldonado-Arocho FJ, Pacheco S, France B, DeGiusti K, Shakir SM, Bradley KA, Ballard JD. Glycogen synthase kinase 3 activation is important for anthrax edema toxin-induced dendritic cell maturation and anthrax toxin receptor 2 expression in macrophages. Infect Immun 79:3302-3308, 2011. [Abstract]

Larabee JL, Shakir SM, Hightower L, Ballard JD. Adenomatous polyposis coli protein associates with C/EBP beta and increases Bacillus anthracis edema toxin-stimulated gene expression in macrophages. J Biol Chem 286:19364-19372, 2011. [Abstract]

Crowe SR, Ash LL, Engler RJ, Ballard JD, Harley JB, Farris AD, James JA. Select human anthrax protective antigen epitope-specific antibodies provide protection from lethal toxin challenge. J Infect Dis 202:251-260, 2010. [Abstract]

Devera TS, Aye LM, Lang GA, Joshi SK, Ballard JD, Lang ML. 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 78:1610-1617, 2010. [Abstract]

Shakir SM, Bryant KM, Larabee JL, Hamm EE, Lovchik J, Lyons CR, Ballard JD. Regulatory interactions of a virulence-associated serine/threonine phosphatase-kinase pair in Bacillus anthracis. J Bacteriol 192:400-409, 2010. [Abstract]

Barua S, McKevitt M, DeGiusti K, Hamm EE, Larabee J, Shakir S, Bryant K, Koehler TM, Blanke SR, Dyer D, Gillaspy A, Ballard JD. The mechanism of Bacillus anthracis intracellular germination requires multiple and highly diverse genetic loci. Infect Immun 77:23-31, 2009. [Abstract]

Joshi SK, Lang GA, Larabee JL, Devera TS, Aye LM, Shah HB, Ballard JD, Lang ML. Bacillus anthracis lethal toxin disrupts TCR signaling in CD1d-restricted NKT cells leading to functional anergy. PLoS Pathog 5:e1000588, 2009. [Abstract]

Nguyen ML, Crowe SR, Kurella S, Teryzan S, Cao B, Ballard JD, James JA, Farris AD. Sequential B-cell epitopes of Bacillus anthracis lethal factor bind lethal toxin-neutralizing antibodies. Infect Immun 77:162-169, 2009. [Abstract]

Nguyen ML, Terzyan S, Ballard JD, James JA, Farris AD. The major neutralizing antibody responses to recombinant anthrax lethal and edema factors are directed to non-cross-reactive epitopes. Infect Immun 77:4714-4723, 2009. [Abstract]

Gut IM, Prouty AM, Ballard JD, van der Donk WA, Blanke SR. Inhibition of Bacillus anthracis spore outgrowth by nisin. Antimicrob Agents Chemother 52:4281-4288, 2008. [Abstract]

Larabee JL, DeGiusti K, Regens JL, Ballard JD. Bacillus anthracis edema toxin activates nuclear glycogen synthase kinase 3beta. Infect Immun 76:4895-4904, 2008. [Abstract]

Stojkovic B, Torres EM, Prouty AM, Patel HK, Zhuang L, Koehler TM, Ballard JD, Blanke SR. High-throughput, single-cell analysis of macrophage interactions with fluorescently labeled Bacillus anthracis spores. Appl Environ Microbiol 74:5201-5210, 2008. [Abstract]

Dodd D, Reese JG, Louer CR, Ballard JD, Spies MA, Blanke SR. Functional comparison of the two Bacillus anthracis glutamate racemases. J Bacteriol 189:5265-5275, 2007. [Abstract]

McKevitt MT, Bryant KM, Shakir SM, Larabee JL, Blanke SR, Lovchik J, Lyons CR, Ballard JD. Effects of endogenous D-alanine synthesis and autoinhibition of Bacillus anthracis germination on in vitro and in vivo infections. Infect Immun 75:5726-5734, 2007. [Abstract]

Salles II, Voth DE, Ward SC, Averette KM, Tweten RK, Bradley KA, Ballard JD. Cytotoxic activity of Bacillus anthracis protective antigen observed in a macrophage cell line overexpressing ANTXR1. Cell Microbiol 8:1272-1281, 2006. [Abstract]

Voth DE, Hamm EE, Nguyen LG, Tucker AE, Salles II, Ortiz-Leduc W, Ballard JD. Bacillus anthracis oedema toxin as a cause of tissue necrosis and cell type-specific cytotoxicity. Cell Microbiol 7:1139-1149, 2005. [Abstract]

Voth DE, Qa’Dan M, Hamm EE, Pelfrey JM, Ballard JD. Clostridium sordellii lethal toxin is maintained in a multimeric protein complex. Infect Immun 72:3366-3372, 2004. [Abstract]

Judith A. James

Eric K. Dumas, Philip M. Cox, Charles O’Conner Fullenwider, Melissa Nguyen, Michael Centola, Mark Barton Frank, Igor Dozmorov, Judith A. James and A. Darise Farris. Anthrax Lethal Toxin-Induced Gene Expression Changes in Mouse Lung. Toxins 2011, 3(9), 1111-1130;[Abstract ]

A. Darise Farris

Mark L. Lang

Devera TS, Joshi SK, Aye LM, Lang GA, Ballard JD, Lang ML. Regulation of anthrax toxin-specific antibody titers by natural killer T cell-derived IL-4 and IFNgamma. PLoS One 6:e23817, 2011. [Abstract]

Patrick Wilson

Di Niro R, Mesin L, Raki M, Zheng NY, Lund-Johansen F, Lundin KE, Charpilienne A, Poncet D, Wilson PC, Sollid LM. Rapid generation of rotavirus-specific human monoclonal antibodies from small-intestinal mucosa. J Immunol 185:5377-5383, 2010. [Abstract]

Wrammert J, Koutsonanos D, Li GM, Edupuganti S, Sui J, Morrissey M, McCausland M, Skountzou I, Hornig M, Lipkin WI, Mehta A, Razavi B, Del RC, Zheng NY, Lee JH, Huang M, Ali Z, Kaur K, Andrews S, Amara RR, Wang Y, Das SR, O’Donnell CD, Yewdell JW, Subbarao K, Marasco WA, Mulligan MJ, Compans R, Ahmed R, Wilson PC. Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 208:181-193, 2011. [Abstract]

Sullivan M, Kaur K, Pauli N, Wilson PC. Harnessing the immune system’s arsenal: producing human monoclonal antibodies for therapeutics and investigating immune responses. F1000 Biol Rep 3:17, 2011. [Abstract]

Kaur K, Sullivan M, Wilson PC. Targeting B cell responses in universal influenza vaccine design. Trends Immunol 32:524-531, 2011. [Abstract]