Inhalational anthrax is the most lethal form of the disease, and the form that occurs when spores ofthe causative agent, 6. anthracis is used as a weapon of bioterror. Uniquely, vegetative bacteria of S. anthracis do not cause disease at the site of entry. Instead spores are taken up by resident lung cells and carried through lymphatic ducts to the thoracic lymph nodes (TLN). From TLN the pathogen disseminates to cause the lethal terminal phase of the disease. There are many unanswered questions about this deadly disease. It is not known what cells take the pathogen out of the lung to the TLN. Most importantly, it is not known what role Ba toxins (lethal toxin, LT; edema toxin, ET) play in this process, and how antibodies to the cellular binding component of these toxins (protective antigen, PA) protect the host. The goal of this proposal is to answer these questions. In the last granting period we determined that in contrast to the prevailing thought, human alveolar macrophages (HAM) do not express cellular receptors for the toxins and are resistant to immunosuppressive effects of LT. We also found that the cells that line the point of entry of the pathogen, alveolar epithelial cells, express anthrax toxin receptors, and are susceptible to the effects of toxin. Toxin decreases barrier function of these cells, which could facilitate escape of the pathogen from the alveolar compartment of the lung. We have characterized three types of human lung dendritic cells (DCs). We hypothesize that one of these is the carrier cell for 6. anthracis, and is unable to kill the pathogen due to toxin.
In Aim 1, we will determine which DCs phagocytose and kill spores, the killing mechanism, and their immune response to spores.
In Aim 2, we will determine whether these cells contain toxin receptors, are immunosuppressed by toxins, and how toxins inhibit, and antibody to PA promotes, killing of pathogen, and the mechanisms involved.
In Aim 3 we will determine whether toxins facilitate carrier cell-assisted, or cell-unassisted escape from the alveolus in an in vitro model. We will also test the role of the carrier cell, and the effect of PA antibody in host protection in a baboon inhalation anthrax model developed by our colleague. Dr. Lupu. Our experiments should confirm whether one site of protective activity of antibodies to PA is in the initial interactions between DCs of the lung and the pathogen. If this is the case, then we should be able to use the results to develop in vitro models to determine efficacy of the antibody response to vaccines. We will also provide new avenues for intervention in this disease.

Public Health Relevance

Anthrax is a significant weapon of bioterror. Symptoms are non-specific, decreasing treatment efficacy. 6. anthracis spores are easy to manufacture and distribute. In contrast, the vaccine is difficult to administer, is of variable efficacy, and it is not known how it protects. Understanding how antibodies to protective antigen protect the host would lead to rapid assays to determine efficacy, allowing efficient vaccine production, and facilitate determination of susceptibility in individuals. It would also provide new opportunifies for intervention.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI062629-11
Application #
8726072
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
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
73117
Morris, D L; Fernando, M M A; Taylor, K E et al. (2014) MHC associations with clinical and autoantibody manifestations in European SLE. Genes Immun 15:210-7
Garman, Lori; Smith, Kenneth; Farris, A Darise et al. (2014) Protective antigen-specific memory B cells persist years after anthrax vaccination and correlate with humoral immunity. Toxins (Basel) 6:2424-31
Garman, Lori; Vineyard, Amanda J; Crowe, Sherry R et al. (2014) Humoral responses to independent vaccinations are correlated in healthy boosted adults. Vaccine 32:5624-31
Lupu, Florea; Keshari, Ravi S; Lambris, John D et al. (2014) Crosstalk between the coagulation and complement systems in sepsis. Thromb Res 133 Suppl 1:S28-31
Joshi, Sunil K; Lang, Mark L (2013) Fine tuning a well-oiled machine: Influence of NK1.1 and NKG2D on NKT cell development and function. Int Immunopharmacol 17:260-6
Lee, Benjamin C; Mayer, Chad L; Leibowitz, Caitlin S et al. (2013) Quiescent complement in nonhuman primates during E coli Shiga toxin-induced hemolytic uremic syndrome and thrombotic microangiopathy. Blood 122:803-6
Dumas, Eric K; Nguyen, Melissa L; Cox, Philip M et al. (2013) Stochastic humoral immunity to Bacillus anthracis protective antigen: identification of anti-peptide IgG correlating with seroconversion to Lethal Toxin neutralization. Vaccine 31:1856-63
Sun, Dawei; Popescu, Narcis I; Raisley, Brent et al. (2013) Bacillus anthracis peptidoglycan activates human platelets through FcýýRII and complement. Blood 122:571-9
Chiu, Christopher; Wrammert, Jens; Li, Gui-Mei et al. (2013) Cross-reactive humoral responses to influenza and their implications for a universal vaccine. Ann N Y Acad Sci 1283:13-21
Smith, Kenneth; Muther, Jennifer J; Duke, Angie L et al. (2013) Fully human monoclonal antibodies from antibody secreting cells after vaccination with Pneumovaxýý23 are serotype specific and facilitate opsonophagocytosis. Immunobiology 218:745-54

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