Genetic Determinants of Host Susceptibility to Pulmonary Anthrax

描述(由申请人提供)：由于炭疽杆菌的现有生物制剂，以及它在被武器化用于吸入暴露时可能导致高死亡率，人们对了解肺炭疽病的发病机制和治疗越来越感兴趣。肺炭疽病通常是双相性的，潜伏性地出现流感样症状，然后迅速恶化，其特征是发展成急性肺损伤，通常会导致致命的后果。目前迫切需要更好地了解炭疽杆菌肺部感染的宿主机制，以及吸入炭疽孢子引起的肺炭疽病的发病机制。除了已知的宿主巨噬细胞对炭疽致死毒素的敏感性外，未知的宿主因素还影响炭疽杆菌的感染和毒力。我们的长期目标是了解宿主对炭疽芽胞诱导的肺炭疽病易感性的遗传因素。我们的假设是，在接触炭疽杆菌引起的肺炭疽病的发展过程中，个体间的差异是由宿主遗传因素控制的，这些因素影响感染过程中的存活时间。我们建议使用多个近交系小鼠品系来研究这一假说。其具体目的是：1)确定近交系小鼠在炭疽芽胞诱导的肺炭疽病发育过程中存活时间的品系间差异；2)寻找与炭疽芽胞诱导的肺炭疽病小鼠存活时间连锁的数量性状基因座(QTL)，并对这些QTL进行电子分析，以便对候选基因进行初步评估。R21的这一努力将是朝着全面未来努力的初步进展，该努力旨在彻底表征新的宿主遗传决定因素，并评估特定候选基因的功能意义，以了解宿主介导的机制，并开发治疗肺炭疽病的新疗法。 这项拟议的研究将有助于了解个体间对肺部炭疽热易感性的遗传基础。科学发展可以改变或加强针对肺炭疽生物感染情况的第一反应和持续临床方法，以及通过确定“危险”人群来改进风险评估。

DESCRIPTION (provided by applicant): Due to the existing biothreat of B. anthracis, and its potential to cause high mortality when weaponized for inhalation exposure, there is an increasing interest in understanding the pathogenesis and treatment of pulmonary anthrax. Pulmonary anthrax is usually biphasic in nature, with an insidious onset of flu-like symptoms, followed by rapid deterioration characterized by the development of acute lung injury, often leading to a fatal outcome. There is a critical need to better comprehend the host mechanisms involved in B. anthracis infection of the lung and the pathogenesis of pulmonary anthrax caused by inhalation of anthrax spores. In addition to the known host macrophage sensitivity to anthrax lethal toxin, unknown host factors influence B. anthracis infection and virulence. Our long-term goal is to understand the genetic factors of host susceptibility to B. anthracis spore-induced pulmonary anthrax. Our hypothesis is that inter-individual variability in the development of pulmonary anthrax from exposure to B. anthracis is controlled by host genetic factors that influence the survival time during the infection process. We propose to use multiple inbred mouse strains to investigate this hypothesis. The Specific Aims are: 1) to determine inter-strain differences between inbred mice for survival time during the development of B. anthracis spore-induced pulmonary anthrax, and 2) to identify quantitative trait loci (QTLs) with linkage to survival time of mice developing B. anthracis spore-induced pulmonary anthrax and in silico analysis of the QTLs for initial assessment of the candidate genes. This R21 effort will constitute an initial progress toward a full future effort to thoroughly characterize novel host genetic determinants, and assess functional significance of specific candidate genes to understand host-mediated mechanisms and develop new therapeutics for the treatment of pulmonary anthrax. The proposed research will help understand the genetic basis of inter-individual susceptibility to pulmonary anthrax. The scientific developments could redirect or strengthen first-response and continuing clinical approaches to a pulmonary anthrax biothreat situation, as well as the improvement of risk assessment through the identification of "at risk" populations.