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.
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.
|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 SjÃ¶gren'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