Genetics Modifiers of Anthrax Lethal Toxin Induced Pathophysiology

炭疽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是共享受体结合亚基PA的催化部分。结果，形成两种二元毒素：由PA和PA组成的致死毒素（LT）。 将纯化的LT注射到动物中诱导许多与暴发性炭疽感染相关的病理，表明该毒素在疾病中起重要作用。然而，对于LT如何导致这些病理缺乏共识。在对LT注射的响应中，在具有CAST/EiJ品系的染色体片段的同类系小鼠中鉴定出快速诱导的表型，所述染色体片段在另外的C57 BL/6 J背景上。我们的证据表明，解释这种早期反应的遗传因素也在对孢子挑战的抗性中起作用，从而确定了这种表型的意义。我们建议研究早期表型，以促进对早期phathophysiological机制的理解，并揭示影响LT诱导的疾病的呈现以及对孢子的抗性的遗传因素。 首先，控制早期敏感性的质量性状基因座（QTL）将通过互补方法（即，定位克隆和表达QTL分析）。 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，早期反应的同类菌株将是一个强大的工具：1）确定遗传因素，调节LT的敏感性，2）阐明与早期LT诱导的事件相关的病理生理机制，和3）揭示防御机制，由主机在响应LT或孢子的挑战。

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.