The present application is the second competing renewal of a CCHI grant first awarded in 2003 to study human immune response to Bacillus anthracis and the toxin vaccine that is currently administered to the thousands of deployed US military. The goals of the original application were: (a) To study the human immune response to a challenging vaccine, (b) To understand the mechanism for the high lethality of the inhalation form of the disease, (c) To understand the cellular basis of the host response to the pathogen. Our published findings show, in contrast to prevailing views, that the high rate of mortality in inhalation anthrax is due to bacterial sepsis and not the anthrax toxins. In the most recent funding cycle, we made the seminal discovery that immune complexes between peptidoglycan (PGN) and pre-existing anti-PGN antibodies present in all humans may be the source of the massive inflammation accompanying infection by B. anthracis. Lastly, we discovered that fully 30% of vaccinees are almost certainly unprotected despite having been immunized more than 6 times in an onerous vaccine schedule. In this renewal application, we will follow up on these exciting discoveries to determine: (a) How do anthrax spores move from the alveoli to the mediastinal lymph nodes. (b) How PGN triggers an antimicrobial response by human immune cells and how anthrax toxins affect the response. (c) How PGN-anti-PGN immune complexes influence the outcome of the disease. (d) Why the vaccine is imperfect in stimulating the maturation of germinal center B cells, and whether elevated histones caused by toxin-impaired efferocytosis contributes to inflammation. Our work is supported by 3 scientific cores: An animal core that applies a non-human primate model established in the previous funding cycle;a flow cytometry core that has state-of-the-art capacity;and a human antibody core that will make recombinant human monoclonal antibodies using technology that was invented at our institute. The studies in this renewal application-are focused and thematically organized around the key roles of PGN, the anthrax toxins and the anthrax toxin vaccine in the human immune responses. They have great potential to identify novel means of interrupting the pathology caused by this model Gram-positive pathogen.

Public Health Relevance

B. anthracis is highly relevant and important agent of bioterrorism. Although a vaccine is provided to military personnel, it is not given to private citizens and is of highly questionable efficacy. We have made great progress in understanding B. anthracis infections in humans and propose novel studies to expand our published findings. Project 1: Toxin-Mediated Suppression of Human PBMC Responses During Bacteremia Project Leader (PL): Ballard, Jimmy DESCRIPTION (provided by applicant): Bacteremia can lead to septic shock and death in infected individuals, yet many aspects of bacteremia remain poorly understood in humans. In particular the host responses to bacterial components and the suppression of these responses by virulence factors in humans mononuclear cells has not been fully investigated and this has limited the development of new therapeutics. Using Bacillus anthracis as a model system we are investigating inflammatory stimuli (peptidoglycan) and modulation of responses to this stimuli by anthrax toxin. In particular we are characterizing the induction of antimicrobials by PGN and studying how anthrax lethal toxin, but not edema toxin, suppresses this response.
The first aim of this project is to characterize the BaPGN-induced antimicrobial response and its modulation by anthrax toxin in human PBMCs.
The second aim i s to characterize the differential mechanisms by which LT and ET modulate inflammatory and antimicrobial responses.
The final aim i s to examine the interplay between BaPGN-induced proinflammatory/antimicrobial factors and their suppression by anthrax toxin in an in vivo model. Completing these aims will address our overall goal of defining the molecular and cellular events occurring between a gram positive pathogen that causes bacteremia and the host responses to that pathogen.

Public Health Relevance

Bacteremia and septic shock are serious medical conditions and treatment options are limited. Results from our studies will provide information about this disease event, with a specific focus on this process in humans and possible ways to treat infected individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI062629-11
Application #
8708258
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Lapham, Cheryl K
Project Start
2004-09-30
Project End
2019-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
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

Showing the most recent 10 out of 105 publications