Pulmonary responses to Bioweapon Category A Pathogens

对生物武器 A 类病原体的肺部反应

• 批准号: 7282054
• 负责人: Clifford RICK LYONS
• 金额: $ 280.56万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7282054
• 关键词: Pulmonary; responses; Bioweapon; Category; Pathogens

DESCRIPTION (provided by applicant): Among the pathogens thought to represent the greatest threat as bioweapons are Bacillus anthracis, Francisella tularensis and smallpox, which are all CDC designated category A pathogens. As bioweapons they are particularly troublesome because they use the pulmonary route and produce diseases that are unusually difficult to diagnose and treat. Further, we know very little about the interaction of these pathogens with the lung environment. The two primary protective options available are: 1) development of vaccines that induce effective acquired immunity against lung infections and/or 2) development of therapeutics that enhance innate immunity. Understanding the mechanisms by which innate and acquired immunity protect against pulmonary challenge with category A pathogens is critical for developing new therapeutics. None of these pulmonary biothreat infections have a high enough incidence in nature to allow us to determine efficacy using standard epidemiological and statistical analysis. Therefore, we must rely heavily on well characterized animal models. We have developed murine pulmonary models for anthrax, virulent tularemia and cowpox virus. We have partnered with Lovelace Respiratory Research Institute to address the interactions of these pathogens with the lung. The Project Leaders of the projects and Cores bring complementary expertise to this Program Project that will provide significant synergy for all of the projects and their aims. Project 1 (Lipscomb) will use defined B. anthracis mutants to investigate the role of the primary virulence factors in dissemination from the lung and induction of end organ damage in murine and nonhuman primate models of inhalation anthrax. It will also investigate the role of alveolar macrophages and complement in preventing dissemination. Project 2 (Pickup) will address the host factors responsible for protection from a pulmonary orthopox virus infection and define the role of poxvirus accessory proteins in pulmonary infections. Project 3 (Lyons) will use a recently developed murine model of LVS vaccination induced protection against a pulmonary infection with Biovar A F. tularensis to define the immune mechanisms responsible for protection. Protective mechanisms identified in the murine model will be compared with those identified in an aerosol exposed nonhuman primate model. In partnership with Macrogenics, we will use Expression Library Immunization to interrogate the F. tularensis genome for vaccine candidates.

描述（由申请人提供）：被认为对生物武器构成最大威胁的病原体包括炭疽杆菌、土拉弗朗西斯菌和天花，它们都是 CDC 指定的 A 类病原体。作为生物武器，它们特别麻烦，因为它们使用肺部途径并产生异常难以诊断和治疗的疾病。此外，我们对这些病原体与肺部环境的相互作用知之甚少。可用的两种主要保护选择是：1）开发诱导针对肺部感染的有效获得性免疫的疫苗和/或2）开发增强先天免疫的疗法。了解先天免疫和后天免疫抵御 A 类病原体肺部攻击的机制对于开发新疗法至关重要。这些肺部生物威胁感染的发病率都没有足够高，无法让我们使用标准流行病学和统计分析来确定疗效。因此，我们必须严重依赖特征良好的动物模型。我们开发了炭疽、强毒兔热病和牛痘病毒的小鼠肺部模型。我们与洛夫莱斯呼吸研究所合作，解决这些病原体与肺部的相互作用。项目和核心的项目负责人为本计划项目带来了互补的专业知识，这将为所有项目及其目标提供显着的协同作用。项目 1（Lipscomb）将使用确定的炭疽芽孢杆菌突变体来研究主要毒力因子在吸入性炭疽的小鼠和非人灵长类动物模型中从肺部传播和诱导终末器官损伤中的作用。它还将研究肺泡巨噬细胞和补体在防止传播中的作用。项目 2（Pickup）将解决负责预防肺部正痘病毒感染的宿主因素，并确定痘病毒辅助蛋白在肺部感染中的作用。项目 3（里昂）将使用最近开发的 LVS 疫苗接种小鼠模型来预防 Biovar A F. tularensis 肺部感染，以定义负责保护的免疫机制。小鼠模型中确定的保护机制将与气溶胶暴露的非人类灵长类动物模型中确定的保护机制进行比较。与 Macrogenics 合作，我们将使用表达库免疫来询问土拉弗朗西斯菌基因组以寻找候选疫苗。