Molecular and Immunologic Analysis of the Pathobiology of Human Anthrax

目前的申请是CCHI关于人类对芽孢杆菌的免疫反应的竞争性更新拨款 炭疽病和保护军队的疫苗，该奖项于2004年首次颁发。世界银行的目标是 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) 了解吸入性疾病致死率高的机制，(C)了解 寄主对病原体反应的细胞基础。我们已经了解了很多关于人类疫苗的知识 收集了近3000份样本，其中包括自然感染B。 炭疽病。尤其值得注意的是，我们发现整整50%的疫苗接种者没有受到保护。情况就是这样，尽管 在繁重的疫苗接种计划中，有超过6种疫苗接种以对抗病原体的毒素。我们有 与流行的观点相反的是，有证据表明，高死亡率是由于细菌败血症，而不是 炭疽毒素。我们取得了开创性的发现，即肽聚糖和预先存在的免疫复合体 存在于所有人类中的血清调理素可能是大规模炎症和凝血障碍的来源。 伴随炭疽杆菌的感染。我们有新的证据表明感染伴随着释放 促炎和促凝血的核小体物质(DAMP)以及炭疽毒素可以调节 这种材料的净空。 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，宿主如何释放湿气，宿主如何清除湿气 宿主的先天免疫系统以及毒素如何影响这些过程。 (B)在疾病的晚期，调理的肽聚糖如何影响疾病的转归。 (C)疫苗在刺激成人生发中心B细胞成熟方面为何不完善。 这些研究得到了两个科学核心的支持：一个应用非人类灵长类动物模型的动物核心 在以前的资金周期中建立，并拥有最先进的分类和分析的流式细胞仪核心 容量。我们也有一个技术开发项目，旨在通过以下方式开发通用模型 哪些病原体，包括炭疽孢子，也包括其他细菌和病毒病原体，在上皮细胞中传播 和内皮屏障来感染组织。 本次续订申请中的研究重点和主题是围绕以下关键角色组织的 肽聚糖和炭疽毒素在人类先天和获得性免疫反应中的作用。他们有很棒的 有可能确定新的方法来阻断这种模式的革兰氏阳性病原体引起的病理。

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.