Molecular and Immunologic Analysis of the Pathobiology of Human Anthrax

本申请是CCHI关于对芽孢杆菌的人类免疫应答的授权的竞争性更新。 炭疽病和保护军队的疫苗，这是在2004年首次授予。的目标 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） （c）了解吸入性疾病的高致命性的机制， 宿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3,000份样本，包括自然感染B的个人样本。 炭疽病特别值得注意的是，我们发现，整整50%的疫苗接种者没有受到保护。这是如此，尽管 在繁重的疫苗接种计划中，针对病原体毒素进行了6次以上的疫苗接种。我们有 与流行观点相反，有证据表明，高死亡率是由于细菌性败血症，而不是 炭疽毒素我们有了开创性的发现，肽聚糖和预先存在的免疫复合物 存在于所有人类中的血清调理素可能是大量炎症和凝血病的来源 伴随B类感染。炭疽病我们有新的证据表明感染伴随着释放 促炎和促凝核小体物质（DAMPs），炭疽毒素可以调节 清除这些材料。 在这次更新申请中，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，它们如何被宿主细胞清除， 宿主先天免疫系统以及毒素如何影响这些过程。 (b)在疾病的晚期，调理肽聚糖如何影响疾病的结局。 (c)为什么疫苗在刺激成人生殖中心B细胞成熟方面不完美。 这些研究得到了两个科学核心的支持：一个是应用非人类灵长类动物模型的动物核心， 在以前的资助周期中建立的流式细胞术核心，具有最先进的分选和分析功能 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，还有其他细菌和病毒病原体， 和内皮屏障来感染组织。 在这个更新应用程序的研究重点和主题组织围绕的关键作用， 肽聚糖和炭疽毒素在人类先天性和适应性免疫反应中的作用。他们有很大 潜在的鉴定中断由该模型革兰氏阳性病原体引起的病理的新手段。

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.