Pulmonary responses to Bioweapon Category A Pathogens

描述(申请人提供)：在被认为是最具威胁的生物武器的病原体中，炭疽芽孢杆菌、图拉氏方济氏菌和天花，都是疾控中心指定的A类病原体。作为生物武器，它们特别麻烦，因为它们使用肺部路线，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。可用的两个主要保护选择是：1)开发可诱导对肺部感染的有效获得性免疫的疫苗和/或2)开发增强天然免疫的治疗方法。了解先天免疫和获得性免疫保护肺免受A类病原体攻击的机制对于开发新的治疗方法至关重要。所有这些肺部生物感染的发病率都不足以让我们使用标准的流行病学和统计分析来确定疗效。因此，我们必须在很大程度上依赖于具有良好特征的动物模型。我们已经建立了炭疽热、毒性图拉热症和牛痘病毒的小鼠肺模型。我们已经与洛夫莱斯呼吸研究所合作，研究这些病原体与肺部的相互作用。项目和核心的项目负责人将为本计划项目带来互补的专业知识，这将为所有项目及其目标提供显著的协同效应。项目1(Lipscomb)将使用已定义的炭疽杆菌突变株来研究主要毒力因子在吸入性炭疽病小鼠和非人类灵长类动物模型中从肺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(皮卡)将解决对肺部正畸病毒感染负责保护的宿主因素，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疫苗诱导的小鼠模型来保护肺部免受Biovar A F.tularens的感染，以确定负责保护的免疫机制。在小鼠模型中发现的保护机制将与在气溶胶暴露的非人类灵长类动物模型中发现的机制进行比较。与MacroGenics合作，我们将使用表达文库免疫来询问图拉氏丝虫的基因组以寻找候选疫苗。

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.