Jimmy D. Ballard, Ph.D.
Edema Toxin Suppression of Immune Responses During Anthrax Disease
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, a pathway generally associated with development. 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.
The full anthrax toxin is made up of three components: protective antigen (PA), edema factor (EF), and lethal factor (LF). ET is comprised of the subunits PA plus EF. A second combination of subunits, PA plus LF combine to form what is referred to as lethal toxin (LT). We are currently investigating the effects of edema toxin (PA plus EF) on innate immune responses, those responses of the immune system that do not require prior infection. We are also determining how ET combines with lethal toxin (LT: PA plus LF) to accomplish this. In addition, we are investigating ET-induced changes in inflammatory responses and intracellular signaling that account for critical immunosuppression during both early stages and late stages of inhalational anthrax as well as characterizing the combined effects of ET and LT on immunosuppression during both early and late stages of anthrax disease.
Bryant-Hudson KM, Shakir SM, Ballard JD. Autoregulatory characteristics of a Bacillus anthracis serine/threonine kinase. J Bacteriol 193:1833-1842, 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]
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]
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]