Jimmy Ballard, PhD

Professor and ChairmanDr. Ballard

Ph.D.: 1993, University of Oklahoma Health Sciences Center

Harvard Medical School
Research Interests: 
Bacterial Pathogenesis, Clostridium difficile, and Bacillus anthracis
Teaching: Molecular Microbiology, Microbial Pathogenesis  

BMSB 1062
Telephone 271-2133
Email: Jimmy-Ballard@ouhsc.edu 




Research Emphasis

In general terms, the study of microbial pathogenesis seeks to understand how microbes damage the host, and in turn how the host attempts to rid the body of the pathogen.  The research in our lab is focused on understanding the mechanisms through which bacterial pathogens damage cells and tissue during disease.  Thus, most of our research is from the perspective of the infecting microbe.  Several bacterial pathogens release soluble proteins, also known as toxins, which inactivate or destroy cells in infected individuals.   The study of bacterial toxins provides insight into how disease occurs and identifies critical areas of therapeutic/vaccine intervention.

Large Clostridial Toxins (LCTs):  LCTs are large single polypeptide proteins that damage host cells by altering cell structure and cell survival.   LCTs transverse target cell membranes and enter the interior of the cell.  Once inside the targeted cell, LCTs glycosylate small GTPases, which are upstream regulators of transcription and cell structure.   Work in our lab focuses on LCTs expressed by Clostridium difficile; this organism is the leading cause of hospital-acquired illness in developed countries.   C. difficile expresses two LCTs (TcdA and TcdB), and the role of these toxins in C. difficile disease is complex. Our lab is currently funded by the National Institutes of Health to better understand the role of these toxins in systemic intoxication.  Simply put, we want to know where these toxins go and what tissue/cells are damaged when they leave the site of infection and enter the bloodstream. The overarching goal of this work is to define the molecular mechanism utilized by these toxins to target a particular cell type and explore how this impacts health.

Anthrax Edema Toxin (ET):  Despite the unmatched publicity over the last 10 years, one important fact about anthrax is hardly ever mentioned; Bacillus anthracis is an extremely interesting pathogen.   B. anthracis infects as a spore, survives inside host cells, germinates, multiplies, and releases toxins, and grows to very high numbers in the bloodstream.  Each of these events is worthy of years of study, and perhaps this is why B. anthracis was one of the first bacteria definitively shown to cause disease.  The paradigms established in those historical experiments have influenced how we study pathogens for over a century now.  Our group is interested in a single fundamental aspect of anthrax disease.  How does this pathogen suppress the host immune system?  This is a critical question because the answer will inform us about the events that support growth of the organism in the bloodstream.  To address this question we have been focusing our efforts on the study of edema toxin (ET) as part of a large program project supported by the National Institutes of Health.    ET suppresses host immune responses by generating high levels of cAMP within the cell.    Our group recently discovered that this event leads to changes in signaling through the Wnt-signaling pathway.  Generally, Wnt signaling is associated with development, and little is known about this pathway in immune responses.  The overarching goal of this work is to define how ET targets the Wnt-signaling pathway and in doing so come to better understand the role of this pathway in host immune responses.

Current Laboratory Personnel:

Garrett Hauck, Research Assistant I

Jonathan Hunt, Ph.D., Postdoctoral Research Fellow

Jason Larabee, Ph.D., Assistant Professor of Research

Sarah Miller, Graduate Research Assistant

Tyler Shadid, Research Assistant I

Selected Publications:

Amino Acid Differences in the 1753-to-1851 Region of TcdB Influence Variations in TcdB1 and TcdB2 Cell Entry. Hunt JJ, Larabee JL, Ballard JD. mSphere. 2017 Aug 2;2(4). pii: e00268-17. doi:10.1128/mSphere.00268-17. eCollection 2017 Jul-Aug.

Intrinsic Toxin-Derived Peptides Destabilize and Inactivate Clostridium difficile TcdB. Larabee JL, Bland SJ, Hunt JJ, Ballard JD. MBio. 2017 May 16;8(3). pii: e00503-17. doi: 10.1128/mBio.00503-17.

Coordination between T helper cells, iNKT cells, and their follicular helper subsets in the humoral immune response against Clostridium difficile toxin B. Rampuria P, Lang GA, Devera TS, Gilmore C, Ballard JD, Lang ML.J Leukoc Biol. 2017 Feb;101(2):567-576. doi: 10.1189/jlb.4A0616-271R.

Memory B Cells Encode Neutralizing Antibody Specific for Toxin B from the Clostridium difficile Strains VPI 10463 and NAP1/BI/027 but with Superior Neutralization of VPI 10463 Toxin B. Devera TS, Lang GA, Lanis JM, Rampuria P, Gilmore CL, James JA, Ballard JD, Lang ML.Infect Immun. 2015 Oct 26;84(1):194-204. doi: 10.1128/IAI.00011-15. 

Exposure of neutralizing epitopes in the carboxyl-terminal domain of TcdB is altered by a proximal hypervariable region. Larabee JL, Krumholz A, Hunt JJ, Lanis JM, Ballard JD. J Biol Chem. 2015 Mar 13;290(11):6975-85. doi: 10.1074/jbc.M114.612184. 

Barua, S, Iyer, JK, Larabee, JL, Raisley, B, Hughes, MA, Coggeshall, KM, Ballard, JD (2013) Toxin Inhibition of Antimicrobial Factors Induced by Bacillus anthracis Peptidoglycan in Human BloodInfection and Immunity, in press

Lanis JM, Heinlen LD, James JA, Ballard JD (2013) Clostridium difficile 027/BI/NAP1 Encodes a Hypertoxic and Antigenically Variable Form of TcdB. PLoS Pathog 9(8): e1003523. doi:10.1371/journal.ppat.1003523

Larabee, J.L., Shakir, S.M., Barua, S., Ballard, JD (2013) Increased cAMP in Monocytes Augments Notch Signaling Mechanisms by Elevating the Recombinant Recognition Sequence Binding Protein at the Jk Site (RBP-J) and Transducin-Like Enhancer of Split (TLE) Journal of Biological Chemistry, in press

Lanis, J., Hightower, L.  and Ballard, JD (2012) TcdB from Hypervirulent Clostridium difficile exhibits increased efficiency of autoprocessing. Molecular Microbiology, 84(1):66-76 PMID: 22372854

Larabee, JL, Maldonado-Arocho, FJ, Pacheco, S, France, B, DeGiusti, K, Shakir, SM, Bradley, KA, Ballard, JD (2011) GSK-3 Activation is Important for Anthrax Edema Toxin Induced Dendritic Cell Maturation and ANTXR2 Expression in Macrophages. Infection and Immunity, 79(8):3302-8.  PMID 21576335

Larabee, JL, Shakir, SM, Hightower, L, and Ballard, JD (2011) Adenomatous polyposis coli protein associates with C/EBP (beta) and increases Bacillus anthracis edema toxin stimulated gene expression in macrophages.  J. Biol. Chem. 286 (22):19364-72 PMID: 21487015

Larabee, JL, Shakir, SM, Hightower, L, and Ballard, JD (2011) Adenomatous polyposis coli protein associates with C/EBP (beta) and increases Bacillus anthracis edema toxin stimulated gene expression in macrophages.  J. Biol. Chem. 286 (22):19364-72 PMID: 21487015

Hudson-Bryant, KM, Shakir, SM, Ballard, JD (2011) Autoregulatory Characteristics of a Bacillus anthracis Serine/Threonine Kinase. J. Bacteriol 193(8): 1833-42 PMID: 21296958

Ballard, J.D. (2010) A Toxin ContestNature, (invited commentary), 467 (7316): 665-6

Lanis, JM, Barua, S, Ballard, JD (2010) Variations in TcdB Activity and the hypervirulence of Emerging Strains of Clostridium difficile. PLoS Pathogens 6(8) PMID: 20808849

Shakir, S.M., Bryant, K.M., Larabee, J.L., Hamm, E.E., Lovchik, J., Lyons, C.R., and Ballard, J.D. (2010) Regulatory Interactions of a Virulence-Associated Serine/Threonine Phosphatase-Kinase Pair in Bacillus anthracis.  Journal of Bacteriology. 192(2): 400-9 PMID: 19926032 

Other Representative Publications (From a total of 72)

Larabee, J.L., DeGiusti, K., Regens, J.L. and J.D. Ballard (2008) Bacillus anthracis Edema Toxin Activates Nuclear Glycogen Synthase Kinase 3bInfection and Immunity, 76: 4895-4904PMID: 18765729

McKevitt, M.T., Bryant, K.M., Shakir, S., Larabee, J.L., Blanke, S.R., Lovchik, J., Lyons, C.R., and J.D. Ballard (2007) Endogenous D-alanine Synthesis and Auto-Inhibition of Bacillus anthracisGermination: Effects on in vitro and in vivo infectionsInfection and Immunity, 75 (12) 5726-5734 PMID: 17923523

E. E. Hamm, D. E. Voth, and J.D. Ballard (2006) Identification of Clostridium difficile TcdB cardiotoxicity using a zebrafish embryo model of intoxicationProceedings of The National Academy of Sciences U S A 103, (38), 14176-81. PMID: 16966605

Salles, I.I., Voth, D.E. Ward, S.C., Averette, K.M., Tweten, R.K., Bradley, K.A., and J.D. Ballard (2006) Cytotoxic Activity of Bacillus anthracis Protective Antigen Observed in a Macrophage Cell Line Overexpressing ANTXR1Cellular Microbiology, (8), 1272-1281  PMID: 16882031

Voth, D., and J.D. Ballard (2005) Clostridium difficile toxins: Mechanism of Action and Role in DiseaseClinical Microbiological Reviews, 18 (2), 247-263 PMID: 15831824

Mourez, M., Yan, M., Lacy, D.B., Dillon, L., Betnsen, L., Marpoe, A., Maurin, C., Hotze, E., Wiggleworth, D., Pimetal, R-A, Ballard, J.D., Collier, R.J. and R. K. Tweten (2003) Mapping Dominant-negative mutations of anthrax protective antigen by scanning mutagenesis. Proceedings of The National Academy of Sciences, 100 (24) 13803-8 PMID:14623961

Salles, I.I., Tucker, Amy. E., Voth D.E. and J.D. Ballard (2003) Toxin-induced resistance in Bacillus anthracis lethal toxin-treated macrophagesProceedings of The National Academy of Sciences 100(21) 12426-12431 PMID: 12864812

Spyres, L.M., Daniel, J., Hensley, A., Qa'Dan, M., Ortiz-Leduc, W., and J.D. Ballard (2003)Mutational Analysis of the Enzymatic Domain of Clostridium difficile Toxin B Reveals Novel Inhibitors of the Wild-Type Toxin.  Infection and Immunity, 71 (6) 3294-3301 PMID:12761111

A full list of publications can be found here.