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
Dumas, Eric K; Garman, Lori; Cuthbertson, Hannah et al. (2017) Lethal factor antibodies contribute to lethal toxin neutralization in recipients of anthrax vaccine precipitated. Vaccine 35:3416-3422
Keshari, Ravi S; Silasi, Robert; Lupu, Cristina et al. (2017) In vivo-generated thrombin and plasmin do not activate the complement system in baboons. Blood 130:2678-2681
Marsman, Gerben; von Richthofen, Helen; Bulder, Ingrid et al. (2017) DNA and factor VII-activating protease protect against the cytotoxicity of histones. Blood Adv 1:2491-2502
Remesh, Soumya G; Andreatta, Massimo; Ying, Ge et al. (2017) Unconventional Peptide Presentation by Major Histocompatibility Complex (MHC) Class I Allele HLA-A*02:01: BREAKING CONFINEMENT. J Biol Chem 292:5262-5270
Healy, Laura D; Puy, Cristina; Fernández, José A et al. (2017) Activated protein C inhibits neutrophil extracellular trap formation in vitro and activation in vivo. J Biol Chem 292:8616-8629
Dumas, Eric K; Gross, Timothy; Larabee, Jason et al. (2017) Anthrax Vaccine Precipitated Induces Edema Toxin-Neutralizing, Edema Factor-Specific Antibodies in Human Recipients. Clin Vaccine Immunol 24:
Wang, Xiaoqiu; Wu, Wenxin; Zhang, Wei et al. (2017) RIG-I overexpression decreases mortality of cigarette smoke exposed mice during influenza A virus infection. Respir Res 18:166
Keshari, Ravi Shankar; Silasi, Robert; Popescu, Narcis Ioan et al. (2017) Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis. Proc Natl Acad Sci U S A :
Patel, Vineet I; Booth, J Leland; Duggan, Elizabeth S et al. (2017) Transcriptional Classification and Functional Characterization of Human Airway Macrophage and Dendritic Cell Subsets. J Immunol 198:1183-1201
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

Showing the most recent 10 out of 109 publications