Agents of Bioterrorism: Pathogenesis and host defense

描述（申请人提供）：人们非常关注在生物恐怖主义的故意行为中重新使用生物制剂的可能性，以及如果重新尝试成为现实，保护公众健康的必要性。为了迎接这一挑战，新的途径的基础研究的发病机制和宿主防御A类剂的生物恐怖主义已经成为可能。在这个计划项目资助申请中，响应生物防御和新兴传染病研究的倡议，一组具有土拉弗朗西斯菌，汉坦病毒和鼠疫耶尔森菌先前经验的科学家将在一个综合项目中合作，该项目将研究：1）生存和复制的机制。巨噬细胞中的鼠疫;项目1，詹姆斯·布利斯卡。2)F.土拉菌与炎症和先天免疫系统细胞的相互作用;项目2，Martha Furie。3)探讨了原核SmpB-SsrA质量控制系统在Y. pestis和F.土拉热，特别强调抗菌治疗及其在抗感染药物发现中的效用;项目3，Wali Karzai。4)调节细胞IFN应答并确定致病性汉他病毒信号通路调节机制的汉他病毒蛋白;项目4，Erich Mackow。5)Y.的毒力因子。pestis和F. tularensis和阐明这些病原体的毒力因子组装和分泌机制;项目5，大卫Thanassi。的 研究项目将得到三个核心的支持。核心A将处理所有行政、开发和实验室安全事务，由PI Jorge Benach领导。核心B是由布鲁斯富彻领导的微阵列和生物信息学核心，将为F. pestis和F. tularensis，并制作定制的人类微阵列。核心B将为所有微阵列实验提供建议和帮助;并与最先进的生物信息学的所有数据解释。核心C将为所有项目生产单克隆抗体。一个多学科的方法，包括在BSL 3Ag设置的小鼠气溶胶感染，预计将成为一个强大的工具，这些代理的基本研究需求，并为发展的诊断和治疗方面的这一计划项目。

DESCRIPTION (provided by applicant): There is much concern about the possibility of renewed use of biological agents in intentional acts of bioterrorism, and the necessity to protect the public's health if renewed attempts were to become a reality. To meet this challenge, new avenues for basic research on the pathogenesis of and host defense to Category A agents of Bioterrorism have become available. In this Program Project Grant application in response to initiatives on Biodefense and Emerging Infectious Disease Research, a group of scientists with previous experience with Francisella tularensis, hantaviruses, and Yersinia pestis will collaborate in a comprehensive project that will study: 1) the mechanisms of survival and replication of Y. pestis in macrophages; Project 1, James Bliska. 2) the novel mechanisms of F. tularensis interaction with cells of the inflammatory and innate immune systems; Project 2, Martha Furie. 3) the biochemical role of the prokaryotic SmpB-SsrA quality control system of Y. pestis and F. tularensis with particular emphasis on antibacterial therapy and its utility in anti-infective drug discovery; Project 3, Wali Karzai. 4) the hantavirus proteins that regulate cellular IFN responses and define mechanisms of signaling pathway regulation by pathogenic hantaviruses; Project 4, Erich Mackow. 5) the virulence factors of Y. pestis and F. tularensis and to elucidate the mechanisms of virulence factor assembly and secretion by these pathogens; Project 5, David Thanassi. The Research Projects will be supported by three Cores. Core A will deal with all administrative, development, and laboratory security matters and it will be headed by the PI, Jorge Benach. Core B is the Microarray and Bioinformatics Core headed by Bruce Futcher will produce spotted DNA microarrays for the genomes of F. pestis and F. tularensis, and make custom human microarrays. Core B will provide advice and assistance with all microarray experiments; and with all data interpretation with state of the art Bioinformatics. Core C will produce monoclonal antibodies for all of the Projects. A multidisciplinary approach including aerosol infections of mice in a BSL3Ag setting is expected to be a powerful tool for the basic research needs of these agents, and for the development of the diagnostic and therapeutic aspects of this Program Project.