Genetic Determinants of Host Susceptibility to Pulmonary Anthrax

描述（由申请人提供）：由于炭疽芽孢杆菌存在的生物威胁，以及它在吸入暴露武器化时可能导致高死亡率，人们对了解肺炭疽芽孢杆菌的发病机制和治疗越来越感兴趣。肺炭疽通常是两期的，发病时表现为隐匿的流感样症状，随后病情迅速恶化，表现为急性肺损伤，往往导致致命的结果。目前迫切需要更好地了解参与肺炭疽杆菌感染的宿主机制以及吸入炭疽孢子引起的肺炭疽的发病机制。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炭疽芽胞杆菌的感染和毒力。我们的长期目标是了解宿主对炭疽杆菌孢子诱导的肺炭疽易感性的遗传因素。我们的假设是，暴露于炭疽芽孢杆菌导致肺炭疽的个体间变异是由宿主遗传因素控制的，这些遗传因素会影响感染过程中的存活时间。我们建议使用多个近交小鼠品系来研究这一假设。具体目的是：1)确定近交系小鼠在炭疽芽孢诱导肺炭疽发病过程中存活时间的株间差异；2)鉴定与炭疽芽孢诱导肺炭疽发病小鼠存活时间连锁的数量性状位点（qtl），并对qtl进行计算机分析，初步评估候选基因。这项R21的研究将构成未来全面研究的初步进展，以彻底表征新的宿主遗传决定因素，评估特定候选基因的功能意义，以了解宿主介导的机制，并开发治疗肺炭疽的新疗法。

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.