Molecular and Immunologic Analysis of the Pathobiology of Human Anthrax

人类炭疽病病理学的分子和免疫学分析

• 批准号: 10239273
• 负责人: Kenneth Mark Coggeshall
• 金额: $ 22.08万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239273
• 关键词: Adult; Affect; Affinity; Agonist; Animal Model; Animals; Anthrax Vaccine Absorbed; Anthrax Vaccines; Anthrax disease; Antibodies; Antigen-Antibody Complex; Antigens; Apoptotic; B-Lymphocytes; Bacillus anthracis; Bacillus anthracis spore; Bacteria; Biological; Blood Coagulation Disorders; Blood coagulation; Cause of Death; Cells; Cessation of life; Collection; Complement; Complement Activation; Dendritic cell activation; Disease; Disease Outcome; Endothelium; Epithelial; Exposure to; Fc Receptor; First Independent Research Support and Transition Awards; Flow Cytometry; Funding; Goals; Grant; Human; IgG4; Immune; Immune response; Immunize; Immunologics; Immunosuppression; Impairment; In Situ; In Vitro; Individual; Infection; Inflammation; Infusion procedures; Inhalation; Innate Immune System; Interruption; Memory B-Lymphocyte; Memory impairment; Military Personnel; Modeling; Molecular; Nuclear Hormone Receptors; Nucleosomes; Oklahoma; Opsonin; Organ failure; Outcome; Papio; Pathology; Pathway interactions; Pattern; Peptidoglycan; Plasmablast; Process; Production; Publishing; Reperfusion Injury; Research Personnel; Role; Sampling; Schedule; Seminal; Sepsis; Serology; Serum; Sorting - Cell Movement; Source; Structure of germinal center of lymph node; Testing; Time; Tissues; Toxin; Vaccinated; Vaccination; Vaccines; Work; adaptive immune response; anthrax toxin; apoptosis in lymphocytes; cohort; follow-up; in vivo; inhibitor/antagonist; mortality; nonhuman primate; novel; pathogen; pathogenic bacteria; pathogenic virus; response; systemic inflammatory response; technology development

The present application is a competing renewal of a CCHI grant on the human immune response to Bacillus anthracis and the vaccine that protects the military, and that was first awarded in 2004. The goals of the original application were threefold: (a) To study the human immune response to a flawed 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. We have learned much about the human vaccine with our collection of nearly 3,000 samples, including samples of individuals who have naturally been infected with B. anthracis. Especially notable is our finding that fully 50% of vaccinees are unprotected. This is so, despite more than 6 vaccinations immunized against the pathogen's toxins in an onerous vaccine schedule. We have evidence, in contrast to prevailing views, that the high rate of mortality is due to bacterial sepsis and not the anthrax toxins. We made the seminal discovery that immune complexes of peptidoglycan and pre-existing serum opsonins present in all humans may be the source of the massive inflammation and coagulopathy accompanying infection by B. anthracis. We have new evidence that the infection is accompanied by release of proinflammatory and procoagulant nucleosome material (DAMPs) and that the anthrax toxins can modulate the clearance of this material. In this renewal application, we will follow up on these exciting discoveries to determine: (a) In the early- and mid-stage of disease, how are DAMPS released by the host, how they are cleared by the host innate immune system and how does toxin affect these processes. (b) In the late stage of the disease, how does opsonized peptidoglycan influence the outcome of the disease. (c) Why the vaccine is imperfect in stimulating the maturation of germinal center B cells in adults. These studies are supported by 2 scientific cores: An animal core that applies a non-human primate model we established in previous funding cycles and a flow cytometry core with state-of-the-art sorting and analyzing capacity. We also have a Technology Development Project that seeks to develop a generalized model by which pathogens, including anthrax spores but also other bacterial and viral pathogens, move across epithelial and endothelial barriers to infect tissue. The studies in this renewal application are focused and thematically organized around the key roles of peptidoglycan and the anthrax toxins in the human innate and adaptive immune responses. They have great potential to identify novel means of interrupting the pathology caused by this model Gram-positive pathogen.

本申请是对人类免疫反应的CCHI赠款的竞争更新 炭疽病和保护军队的疫苗，该疫苗于2004年首次授予。 原始应用是三重的：（a）研究人类对有缺陷疫苗的免疫反应，（b）对 了解疾病吸入形式高致死性的机制，（c）了解 宿主对病原体反应的细胞基础。我们已经学到了很多关于人类疫苗的知识 收集了近3,000个样本，包括自然感染B的个体样本。 炭疽菌。我们的发现特别值得注意的是，完全50％的疫苗受到保护。是如此，尽管 在繁重的疫苗时间表中针对病原体的毒素进行了6种以上的疫苗接种。我们有 与普遍观点相比，有证据表明，高死亡率是由于细菌败血症而不是引起的 炭疽毒素。我们进行了开创性的发现，即肽聚糖的免疫复合物和现有的 所有人类中存在的血清调子素可能是大规模炎症和凝血病的根源 炭疽芽孢杆菌伴随感染。我们有新的证据表明感染伴随着释放 促炎和促凝核小体材料（湿），炭疽毒素可以调节 清除此材料。 在此续订应用程序中，我们将跟进这些令人兴奋的发现以确定： （a）在疾病的早期和中期，宿主如何释放潮湿，如何清除它们 宿主先天免疫系统以及毒素如何影响这些过程。 （b）在疾病的后期，调子化肽聚糖如何影响疾病的结果。 （c）为什么该疫苗在刺激成年人中生发中心B细胞的成熟中不完美。 这些研究得到了2种科学核心的支持：应用非人类灵长类动物模型的动物核心我们 在先前的资金周期和带有最新分类和分析的流式细胞仪核心中建立 容量。我们还拥有一个技术开发项目，试图通过 哪些病原体，包括炭疽孢子，以及其他细菌和病毒病原体，都在上皮上移动 以及感染组织的内皮障碍。 该更新应用中的研究集中于此，并围绕着主题组织 肽聚糖和人类先天和适应性免疫反应中的炭疽毒素。他们很棒 识别中断该模型革兰氏阳性病原体引起的病理的新型方法的潜力。