Genetics Modifiers of Anthrax Lethal Toxin Induced Pathophysiology

炭疽芽孢杆菌的毒力与三种质粒编码的毒素蛋白的分泌有关：保护性抗原(PA)、致死因子(LF)和水肿因子(EF)。LF和EF是共用受体结合亚单位PA的催化部分。结果形成了两种二元毒素：由PA和PA组成的致死毒素(LT) 将纯化的LT注射到动物体内可诱导许多与雷暴炭疽病感染相关的病理变化，这表明这种毒素在疾病中起着重要作用。然而，关于LT是如何导致这些病理的，目前还缺乏共识。作为对LT注射的响应，在C57BL/6J背景上具有CAST/EIJ株染色体片段的同源品系小鼠中发现了快速诱导的表型。我们的证据表明，解释这种早期反应的遗传因素(S)也在抵抗孢子挑战方面发挥作用，从而确立了这种表型的意义。我们建议研究LT的早期表型，以促进对早期生理机制的了解，并揭示影响LT诱导的疾病和对孢子的抗性的遗传因素。 首先，通过互补的方法(即位置克隆和表达QTL分析)定位控制早期敏感性的质量性状基因座(QTL)。 其次，驱动早期表型的病理生理机制将通过包括活体显微镜和药理学方法的研究来确定。 总之，早期响应的同源菌株将是一个强有力的工具：1)鉴定调节LT敏感性的遗传因素，2)阐明与LT早期诱导事件相关的病理生理机制，3)揭示寄主对LT或孢子攻击的防御机制。

Virulence of Bacillus anthracis is associated with the secretion of three plasmid-encoded toxin proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). LF and EF are catalytic moieties that share the receptor-binding subunit, PA. As a result, two binary toxins are formed: lethal toxin (LT) consisting of PA and Injection of purified LT into animals induces many of the pathologies associated with fulminate anthrax infection indicating that this toxin plays a significant role in disease. However, there is a lack of consensus about how LT causes these pathologies. In response to LT injection, a rapidly induced phenotype was identified in a congenic strain of mice that has a chromosomal segment of the CAST/EiJ strain on an otherwise C57BL/6J background. Our evidence indicates that the genetic factor(s) accounting for this early response also plays role in resistance to spore challenge establishing the significance of this phenotype. We propose to study the early phenotype of advance the understanding of early phathophysiolgical mechanisms and to reveal genetic factors that influence the presentation of LT induced disease well as resistance to spores. First, the qualitative trait loci (QTL) controlling early sensitivity will be mapped by complimentary approaches (i.e., positional cloning and expression QTL analysis). Second, the pathophysiological mechanism driving the early phenotype will be determined by studies that include intravital microscopy and pharmacological approaches. In summary, the early responding congenic strain will be a powerful tool for: 1) identifying genetic factors that regulate sensitivity to LT, 2) elucidating the pathophysiological mechanisms associated with early LT-induced events, and 3) revealing defense mechanisms that are employed by the host in response to LT or spore challenge.