Anthrax disease progresses from initial infection to serious systemic illness due to the ability of Bacillus anthracis to avoid clearance by the host immune system. Anthrax toxin, composed of protective antigen (PA), edema factor (EF), and lethal factor (LF), is a major contributing factor to disease as the toxin suppresses immune cell function. Thus, insights into the mechanism of action for anthrax toxin provides critical information necessary for understanding the pathogenesis of B. anthracis. In the current project experiments are designed to elucidate the effects of edema toxin (ET: PA plus EF) on innate immune responses, and determine how ET combines with lethal toxin (LT: PA plus LF) to accomplish this process. After translocation into the cell by PA, EF functions as an adenylate cyclase and generates high levels of cAMP. In recent studies we have discovered that ET activates glycogen synthase kinase-3|3 (GSK- 3(3) leading to inactivation p-catenin and loss in (3-catenin cotranscriptional regulation. The goal of these studies are now to elucidate the impact ET-mediated disruption immune cell function and the effects of this process on human alveolar macrophages and peripheral blood mononuclear cells, as well as determine the combined effects of ET and LT on these cells.
The specific aims of this project are:
Specific Aim 1 : We will characterize the ET-induced changes in inflammatory responses and intracellular signaling that account for critical immunosuppression during early stages of inhalational anthrax Specific Aim 2: We will characterize the ET-induced changes in inflammatory responses and intracel signaling that account for critical immunosuppression during late stages of inhalational anthrax Specific Aim 3: We will characterize the combined effects of ET and LT on immunosuppression during both early and late stages of anthrax disease.

Public Health Relevance

Anthrax is a major threat to the health of US population, because of the potential nefarious use of B. anthracis by bioterrorist. Anthax has a high mortality rate, despite various treatment options. Thus it continues to be essential to understand the basic mechanisms of B. anthracis virulence. For this reason the proposed studies are highly relevant as findings from this work will help better understand immune suppression during disease and identify new avenues for prophylatic and therapeutic treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI062629-09
Application #
8379006
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
9
Fiscal Year
2012
Total Cost
$332,555
Indirect Cost
$55,812
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Liu, Ke; Kurien, Biji T; Zimmerman, Sarah L et al. (2016) X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome. Arthritis Rheumatol 68:1290-300
Garman, Lori; Smith, Kenneth; Muns, Emily E et al. (2016) Unique Inflammatory Mediators and Specific IgE Levels Distinguish Local from Systemic Reactions after Anthrax Vaccine Adsorbed Vaccination. Clin Vaccine Immunol 23:664-71
Hu, Zihua; Jiang, Kaiyu; Frank, Mark Barton et al. (2016) Complexity and Specificity of the Neutrophil Transcriptomes in Juvenile Idiopathic Arthritis. Sci Rep 6:27453
Devera, T Scott; Lang, Gillian A; Lanis, Jordi M et al. (2016) 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. Infect Immun 84:194-204
McMurtrey, Curtis; Trolle, Thomas; Sansom, Tiffany et al. (2016) Toxoplasma gondii peptide ligands open the gate of the HLA class I binding groove. Elife 5:
Wu, Wenxin; Zhang, Wei; Booth, J Leland et al. (2016) Human primary airway epithelial cells isolated from active smokers have epigenetically impaired antiviral responses. Respir Res 17:111
Booth, J Leland; Duggan, Elizabeth S; Patel, Vineet I et al. (2016) Bacillus anthracis spore movement does not require a carrier cell and is not affected by lethal toxin in human lung models. Microbes Infect 18:615-626
Smith, Kenneth; Shah, Hemangi; Muther, Jennifer J et al. (2016) Antigen nature and complexity influence human antibody light chain usage and specificity. Vaccine 34:2813-20
Patel, Vineet Indrajit; Metcalf, Jordan Patrick (2016) Identification and characterization of human dendritic cell subsets in the steady state: a review of our current knowledge. J Investig Med 64:833-47
Kovats, S; Turner, S; Simmons, A et al. (2016) West Nile virus-infected human dendritic cells fail to fully activate invariant natural killer T cells. Clin Exp Immunol 186:214-226

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