Pacific-Southwest Ctr for Biodefense & Emerg Infect Dis*

描述(由申请人提供)：太平洋-西南生物防御和新发传染病研究中心将是一个由亚利桑那州、加利福尼亚州、夏威夷和内华达州的几个公共和私人机构的研究人员组成的合作和协同的联盟。该中心的总体目标如下：(1)对具有生物防御或新出现的公共卫生重要性的传染病进行杰出的多学科合作研究；(2)在区域卓越中心网络内以及向地方、州和联邦机构传播研究成果和试剂；(3)及时将研究成果转化为检测、监测、预防和治疗这些感染的产品和应用；(3)公平地为新的研究人员提供进入该领域的机会，并制定创新的培训计划，以加强生物防御的准备；以及(4)随时待命应对生物恐怖主义威胁和新出现的传染病紧急情况。将有8个项目，每个项目包括3-5个研究项目，以及支持这些项目的6个不同的核心技术设施。这些项目的研究领域是炭疽疫苗、虫媒病毒、虫媒病毒、肉毒杆菌毒素、伯克霍尔德氏菌、汉坦病毒、鼠疫和图拉热症。核心设施包括动物模型、临床试验、质谱学和蛋白质组学、DNA微阵列、病原体检测新技术和全基因组蛋白质阵列。衡量成果的主要标准如下：(A)科学的质量和创新性，以及在多大程度上产生了新的研究基金和合同；(B)是否达到了将研究成果转化为产品或其他应用的里程碑；(C)在生物防御研究领域增加了新的研究人员，并与州和联邦实验室和工业建立了新的合作关系；(D)准备好应对紧急情况。 项目1：炭疽病：针对炭疽芽孢杆菌胶囊进行免疫保护(Kozel，T.R.) 项目1说明(由申请人提供)：播散性炭疽病的特点是大量菌血症和毒血症。细菌相是由于存在防止细菌吞噬的聚伽马-D-谷氨酸(PGA)的胶囊多肽而成为可能的。目前预防吸入性炭疽病的策略是通过PA免疫来针对毒素。靶向PA很有可能是免疫保护所必需的，但还不够。该计划以PGA为目标，旨在减少或消除毒素血症之前的菌血症。因此，有机会在胶囊和毒素靶向免疫之间产生强大的协同作用。初步研究开发了针对PGA的单抗，并证明在小鼠肺炭疽病模型中具有高水平的保护作用。更多的初步研究表明，PGA是一种T非依赖性抗原，通过与免疫原性蛋白载体的结合，其免疫原性显著提高。为这一计划提出的研究将进一步检查胶囊靶向免疫的免疫学基础和影响这种免疫的因素。项目1(Kozel)将使用PGA特异性单抗检查包膜结构和包膜-抗体相互作用的免疫化学，并将在体外确定体内保护的替代物。项目2(Lucas)将优化蛋白质结合疫苗的配方，并将表征对候选疫苗的免疫反应。项目3(Murphy)将评估CD40激动剂抗体的使用，以诱导对PGA的快速IgG抗体反应，用于暴露后免疫。项目4(KEIM)将利用世界上最大的已知和特征最好的炭疽杆菌分离物来检查胶囊生产和胶囊基因表达方面的菌株多样性。项目5将使用小鼠和兔的肺炭疽模型来评估针对胶囊的主动免疫和被动免疫，以及菌株多样性在胶囊靶向免疫中的作用。总之，这些研究将检查炭疽-胶囊结构的生物学和免疫学方面，抗体-胶囊相互作用的分子基础，胶囊的免疫原性，以及胶囊靶向主动免疫和被动免疫的有效性。

DESCRIPTION (provided by applicant): The Pacific-Southwest Center for Biodefense and Emerging Infectious Diseases Research will be a collaborative and synergistic consortium of investigators at several public and private institutions in Arizona, California, Hawaii, and Nevada. The overall goals of the Center are the following: (1) outstanding multidisciplinary and collaborative research on infectious diseases of biodefense or emerging public health importance; (2) secure dissemination of research findings and reagents within the Regional Centers for Excellence network and to local, state, and federal agencies; (3) timely translation of research findings into products and applications to detect, monitor, prevent, and treat these infections; (3) equitable provision of opportunities for new investigators to enter the field and development of innovative training programs to enhance biodefense readiness; and (4) on-call preparedness to respond to bioterrorism threats and emerging infectious disease emergencies. There will be eight program projects, each comprising 3-5 research projects, and six different core technology facilities in support of the programs. The research areas of the programs are anthrax vaccines, arboviruses, arenaviruses, botulinum toxin, Burkholderia, hantaviruses, plague, and tularemia. The cores facilities are animal models, clinical trials, mass spectroscopy and proteomics, DNA microarrays, new technologies for pathogen detection, and genome-wide protein arrays. The major criteria for outcome measurements are the following: (a) the quality and innovativeness of the science, as well as the extent to which new research funds and contracts are generated; (b) whether the milestones for translating research findings into products or other applications are attained; (c) the addition of new investigators in the field of biodefense research and the establishment of new collaborations with state and federal laboratories and industry; and (d) readiness for an emergency response. PROJECT 1: ANTHRAX: TARGETING THE BACILLUS ANTHRACIS CAPSULE FOR IMMUNOPROTECTION (Kozel, T. R.) PROJECT 1 DESCRIPTION (provided by applicant): Disseminated anthrax is characterized by both a massive bacteremia and toxemia. The bacteremic phase is made possible by the presence of a capsular polypeptide of poly-gamma-D-glutamic acid (PGA) that prevents phagocytosis of the bacterium. Current strategies for prevention of inhalation anthrax target the toxin through immunization with PA. There is a good possibility that targeting PA may be necessary but not sufficient for immunoprotection. This program targets PGA with the intent of reducing or eliminating the bacteremia that precedes toxemia. Thus, there is an opportunity for potent synergy between capsule- and toxin-targeted immunity. Preliminary studies developed monoclonal antibodies (mAbs) specific for PGA and demonstrated a high level of protection in a murine model of pulmonary anthrax. Additional preliminary studies demonstrated that PGA is a T-independent antigen whose immunogenicity is markedly increased by conjugation to an immunogenic protein carrier. Studies proposed for this program will examine further the immunologic basis of capsule-targeted immunity and the factors that influence such immunity. Project 1 (Kozel) will examine capsular architecture and the immunochemistry of capsule-antibody interactions using PGA-specific mAbs and will identify in vitro surrogates of protection in vivo. Project 2 (Lucas) will optimize formulation of a protein conjugate vaccine and will characterize the immune response to candidate vaccines. Project 3 (Murphy) will evaluate use of a CD40 agonist antibody to induce a rapid IgG antibody response to PGA for post-exposure immunization. Project 4 (Keim) will take advantage of the world's largest known and best characterized collection of B. anthracis isolates to examine strain diversity in capsule production and capsular gene expression. Project 5 will use murine and rabbit models of pulmonary anthrax to evaluate active and passive immunization that targets the capsule and the role of strain diversity in capsule-targeted immunity. Together, these studies will examine dramatically understudied aspects of the biology and immunology of anthrax-capsule structure, the molecular basis of antibody-capsule interactions, immunogenicity of the capsule, and the efficacy of capsule-targeted active, and passive immunization.