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，它们共享 受体结合亚单位PA。结果，形成了两种二元毒素：由PA组成的致命毒素(LT) 以及由PA和EF组成的水肿性毒素(ET)。将纯化的LT注射到动物体内可以诱导许多 与雷暴炭疽病感染相关的病理表明，这种毒素在 疾病。然而，关于LT是如何导致这些病理的，目前还缺乏共识。对LT的响应 注射后，在具有染色体的同源品系小鼠中鉴定出一种快速诱导的表型。 其他C57BL/6J背景上的CAST/EIJ应变片段。对该菌株的研究将推进该菌株的研究 理解早期病理生理变化的机制并揭示遗传因素(S) 影响LT诱导的疾病。此外，这种菌株从急剧下降中恢复过来，只剩下 随后屈服于LT。戏剧性的恢复为调查主机响应提供了一个独特的窗口 抑制或对抗LT诱导的疾病。我们建议对这些患者的早期LT反应表型进行研究 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 具有最终目标的方法(即候选基因、位置克隆和表达QTL分析) 是导致早期表型的基因(S)的鉴定。第二，病理生理学 驱动早期表型的机制，以及从早期表型恢复的机制，将通过以下研究来确定 活体显微镜、骨髓移植、病理和临床化学图谱和基因芯片 专注于恢复阶段、压力反应途径的阵列。总而言之，早期的反应 同源菌株将是一个强大的工具：1)识别调节LT敏感性的遗传因素，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 主机为响应LT而采用的防御机制。

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.