Genetic Determinants of Host Susceptibility to Pulmonary Anthrax

描述（由申请人提供）：由于B存在生物威胁。由于炭疽病的发病机制及其在武器化吸入暴露时造成高死亡率的可能性，人们对了解肺炭疽病的发病机制和治疗越来越感兴趣。肺炭疽通常是双相性的，具有流感样症状的潜伏发作，随后以急性肺损伤的发展为特征的快速恶化，通常导致致命的结果。迫切需要更好地理解B中涉及的宿主机制。肺炭疽感染和吸入炭疽孢子引起肺炭疽的发病机制。除了已知的宿主巨噬细胞对炭疽致死毒素的敏感性外，未知的宿主因素影响B。炭疽感染和毒力。我们的长期目标是了解宿主对B易感性的遗传因素。炭疽孢子引起的肺炭疽。我们的假设是，暴露于B导致肺炭疽病的发展存在个体间差异。炭疽病受宿主遗传因素控制，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设。具体目的是：1）确定近交系小鼠在B发育过程中存活时间的品系间差异。炭疽孢子诱发的肺炭疽; 2）鉴定与发育B型小鼠存活时间连锁的数量性状基因座（QTL）。炭疽孢子诱导的肺炭疽病和计算机分析的QTL的候选基因的初步评估。这项R21的努力将构成一个全面的未来努力的初步进展，以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，并开发新的治疗方法治疗肺炭疽。 这项拟议的研究将有助于了解个体间对肺炭疽易感性的遗传基础。科学发展可以调整或加强对肺炭疽生物威胁情况的第一反应和持续临床方法，并通过确定“风险”人群改进风险评估。

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.