VIRULENCE GENE EXPRESSION BY BACILLUS ANTHRACIS

描述(改编自申请者的摘要)：成功 病原体，细菌必须具有感知特定宿主的机制 环境，处理变化，并做出适当的适应。在……里面 许多细菌，不同毒力因子的表达受一种 共同的监管体系。毒力基因在炭疽杆菌中的表达， 炭疽病的致病因子，是一个独特的例子 对特定宿主相关信号的调节反应。强毒芽孢杆菌 炭疽菌产生两种已知的致病因子，一种三方毒素，由 包括水肿因子、致死因子和保护性抗原，以及 聚-D-谷氨酸胶囊。毒素和衣壳基因位于 PXO1(185kb)和pXO2(95kb)。这些化合物的合成 当炭疽杆菌生长水平较高时，毒力因子会增强 二氧化碳的排放。二氧化碳被认为具有重要的生理意义。 在炭疽感染期间发出信号。水中重碳酸盐和二氧化碳的浓度 哺乳动物的组织与激活毒素和被膜的组织相似 在体外生长过程中的合成。 这些研究的长期目标是阐明 炭疽杆菌毒力基因的表达。公安局已确定 反式作用调控基因AtxA是二氧化碳诱导转录所必需的 三种毒素基因在体外生长过程中的差异。Atxa还能激活毒素 在体内表达；AtxA突变体对小鼠和感染的小鼠是无毒的 与Atxa-菌株表现出对毒素的免疫反应降低 蛋白质。另一种基因ACPA与二氧化碳诱导的胶囊有关 基因表达。在本研究中，PI将进一步探讨其对 毒素和胶囊的合成，并调查炭疽杆菌是否藏有 额外的毒力基因。具体目标是：1)确定 AtxA调控的非毒素基因，并检测这些基因对 毒力；2)识别和表征额外的调控基因 影响毒素表达，3)探讨其生理意义。 ACPA在含AtxA的细胞中的表达。这些研究将提供 与炭疽病发病机制相关的信息和增加 关于寄主-寄生虫关系和信号转导的知识。

DESCRIPTION (Adapted from the applicant's abstract): To be successful pathogens, bacteria must possess mechanisms for sensing specific host environments, processing changes, and making appropriate adaptations. In many bacteria, expression of disparate virulence factors is controlled by a common regulatory system. Virulence gene expression in Bacillus anthracis, the causative agent of anthrax, is a unique example of a coordinately regulated response to a specific host-related signal. Virulent Bacillus anthracis produce two known virulence factors, a tripartite toxin, composed of edema factor, lethal factor, and protective antigen, and a poly-D-glutamic acid capsule. The toxin and capsule genes are located on plasmids pXO1 (185 kb) and pXO2 (95 kb), respectively. Synthesis of these virulence factors is enhanced when B. anthracis is grown in elevated levels of carbon dioxide. CO2 is postulated to be a physiologically significant signal during anthrax infection. Concentrations of bicarbonate and CO2 in mammalian tissues are comparable to those that activate toxin and capsule synthesis during in vitro growth. The long term goal of these studies is to elucidate the molecular basis for virulence gene expression in B. anthracis. The PI has determined that the trans-acting regulatory gene atxA is required for CO2-induced transcription of all three toxin genes during growth in vitro. AtxA also activates toxin expression in vivo; atxA mutants are avirulent in mice and mice infected with atxA- strains show a decreased immunological response to the toxin proteins. Another gene, acpA, has been implicated in CO2-induced capsule gene expression. In this study, the PI will further probe regulation of toxin and capsule synthesis and investigate whether B. anthracis harbors additional virulence genes. The specific aims are to: 1) identify atxA-regulated non-toxin genes and test the effect of these genes on virulence; 2) identify and characterize additional regulatory genes that affect toxin expression, 3) investigate the physiological significance of acpA expression in cells harboring atxA. These studies will provide information relevant to the pathogenesis of anthrax disease and increase knowledge concerning host-parasite relationships and signal transduction.