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: 10264258
• 负责人: Kenneth Mark Coggeshall
• 金额: $ 91.68万
• 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: 2020-06-08 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264258
• 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; Epithelium; 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; Serological; 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; 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.

本申请是关于人类对芽孢杆菌免疫反应的 CCHI 拨款的竞争更新 炭疽病和保护军队的疫苗，该疫苗于 2004 年首次授予。 最初的应用有三个方面：（a）研究人类对有缺陷的疫苗的免疫反应，（b） 了解该疾病吸入形式高致死率的机制，(c) 了解 宿主对病原体反应的细胞基础。我们已经对人类疫苗有了很多了解 收集了近 3,000 个样本，其中包括自然感染 B. 炭疽病。尤其值得注意的是，我们发现 50% 的疫苗接种者没有受到保护。事情就是这样，尽管 在繁重的疫苗接种计划中，针对病原体的毒素进行了 6 次以上的疫苗接种。我们有 与普遍观点相反，有证据表明高死亡率是由于细菌性败血症而不是细菌性败血症造成的。 炭疽毒素。我们做出了开创性的发现，即肽聚糖和预先存在的免疫复合物 所有人类中存在的血清调理素可能是大规模炎症和凝血病的根源 伴随炭疽杆菌感染。我们有新的证据表明感染伴随着释放 促炎和促凝血核小体物质 (DAMP) 以及炭疽毒素可以调节 该材料的清关。 在此续订申请中，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DAMPS，如何被机体清除 宿主先天免疫系统以及毒素如何影响这些过程。 (b)在疾病晚期，调理后的肽聚糖如何影响疾病的结果。 (c) 为什么疫苗在刺激成人生发中心 B 细胞成熟方面不完善。 这些研究得到 2 个科学核心的支持： 动物核心应用了我们研究的非人类灵长类动物模型 在之前的融资周期中建立的流式细胞术核心具有最先进的分类和分析能力 容量。我们还有一个技术开发项目，旨在开发一个通用模型 哪些病原体（包括炭疽孢子以及其他细菌和病毒病原体）穿过上皮细胞 和感染组织的内皮屏障。 此更新应用程序中的研究重点围绕以下关键角色进行主题组织： 肽聚糖和炭疽毒素在人类先天和适应性免疫反应中的作用。他们有很棒的 潜在地确定中断由该模型革兰氏阳性病原体引起的病理学的新方法。