VIRULENCE GENE EXPRESSION BY BACILLUS ANTHRACIS

描述（改编自申请人的摘要）：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，并做出适当的调整。 在 在许多细菌中，不同的毒力因子的表达是由 共同监管制度。 炭疽芽孢杆菌毒力基因的表达， 炭疽的病原体，是一个独特的例子， 对特定宿主相关信号的调节反应。 毒性芽孢杆菌 炭疽产生两种已知的毒力因子，一种三重毒素， 水肿因子、致死因子和保护性抗原，以及 聚D-谷氨酸胶囊 毒素和荚膜基因位于 质粒pXO 1（185 kb）和pXO 2（95 kb）。 合成这些 当B.炭疽菌的生长水平 二氧化碳。 二氧化碳被认为是一种生理上重要的 炭疽感染期间的信号。 碳酸氢盐和CO2的浓度 哺乳动物组织与那些激活毒素和荚膜的组织相当， 在体外生长期间合成。 这些研究的长期目标是阐明 毒力基因在B中的表达。炭疽病 PI已确定， CO2诱导的转录需要一个反式调节基因atxA 所有三种毒素基因在体外生长过程中。 AtxA也能激活毒素 在体内表达; atxA突变体在小鼠和感染的小鼠中无毒力 atxA-菌株对毒素的免疫反应降低 proteins. 另一个基因acpA与CO2诱导的荚膜形成有关， 基因表达。 在这项研究中，PI将进一步探索 毒素和胶囊合成，并调查是否B。炭疽港 其他毒力基因 具体目标是：（1）确定 atxA调节的非毒素基因，并测试这些基因对 毒力; 2）鉴定和表征另外的调节基因， 影响毒素的表达，3）研究 acpA在携带atxA的细胞中的表达。 这些研究将提供 有关炭疽病发病机理的资料， 关于宿主-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.