Genetics Modifiers of Anthrax Lethal Toxin Induced Pathophysiology

摘要 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是催化部分， 受体结合亚单位PA。结果，形成两种二元毒素：由PA组成的致死毒素（LT）， 和LF;水肿毒素（ET）由PA和EF组成。将纯化的LT注射到动物体内可诱导许多 与暴发性炭疽感染相关的病理学表明，这种毒素在 疾病然而，对于LT如何导致这些病理缺乏共识。针对LT 注射后，在具有染色体畸变的同类系小鼠中鉴定出快速诱导的表型。 在另外的C57 BL/6 J背景上的CAST/EiJ菌株的片段。对该菌株的研究将推动 了解早期病理生理变化的机制，并揭示遗传因素 影响LT诱导的疾病。此外，这种菌株从急剧下降中恢复过来， 随后屈服于LT。戏剧性的恢复提供了一个独特的窗口，调查主机的反应 抑制或对抗LT诱导的疾病。我们建议研究这些患者的早期LT反应表型， 动物首先，控制早期敏感性的质量性状基因座（QTL）将通过互补定位来定位。 方法（即，候选基因、定位克隆和表达QTL分析）与最终目的 即鉴定负责早期表型的基因。第二，病理生理学 驱动早期表型的机制，以及从中恢复，将通过以下研究来确定，包括 活体显微镜、骨髓移植、病理和临床化学特征和基因芯片 阵列专注于恢复阶段，应激反应途径。总之，早期反应 同源株将是一个强大的工具：1）确定遗传因素，调节敏感性LT，2） 阐明与早期LT诱导事件相关的病理生理机制，以及3）揭示 防御机制是由主机响应LT。

ABSTRACT 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 LF, and edema toxin (ET) consisting of PA and EF. 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. Study of this strain will advance the understanding of the mechanism(s) underlying early pathophysiological changes and reveal genetic factors that influence LT induced disease. In addition, this strain recovers from their precipitous decline only to subsequently succumb to LT. The dramatic recovery provides a unique window to investigate host responses that suppress or counter LT induced disease. We propose to study the early LT-response phenotype in these animals. First, the qualitative trait loci (QTL) controlling early sensitivity will be mapped by complimentary approaches (i.e., candidate gene, positional cloning, and expression QTL analysis) with the eventual Objective being the identification of the gene(s) responsible for the early phenotype. Second, the pathophysiological mechanism driving the early phenotype, and recovery from it, will be determined by studies that include intravital microscopy, bone marrow transplantation, pathological and clinical chemistry profiles, and gene chip arrays that are focused on recovery phase, stress response pathways. 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.