Agents of Bioterrorism: Pathogenesis and host defense

描述（由申请人提供）：人们非常关注在蓄意的生物恐怖主义行为中再次使用生物制剂的可能性，以及如果再次尝试成为现实，保护公众健康的必要性。为了应对这一挑战，生物恐怖主义A类制剂的发病机制和宿主防御的基础研究开辟了新的途径。为了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氏菌研究经验的科学家将在一个综合项目中合作，研究：1)鼠疫耶尔森氏菌在巨噬细胞中的生存和复制机制；2)土拉菌与炎症和先天免疫系统细胞相互作用的新机制；3)鼠疫杆菌和土拉菌原核SmpB-SsrA质量控制系统的生物化学作用，重点是抗菌治疗及其在抗感染药物开发中的应用；4)调节细胞IFN反应的汉坦病毒蛋白，并确定致病性汉坦病毒调控信号通路的机制；5)鼠疫耶尔森菌和土拉菌的毒力因子及其在病原菌中组装和分泌毒力因子的机制；五号计划，大卫·塔纳西。这个

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.