Analyzing Anthrox Toxins in Drosophila

描述(申请人提供)：细菌病原体及其产生的毒素是发展中国家疾病和死亡的主要原因，可用作生物恐怖主义的媒介。由于许多毒素的宿主靶蛋白在进化过程中是高度保守的，模式生物如黑腹果蝇为分析毒素作用的分子机制和寻找新的宿主靶标介导其毒性提供了有效的工具。 炭疽芽孢杆菌是炭疽病的病原体，它产生两种外毒素，即致死因子(Lf)和水肿因子(EF)，这是细菌致病所必需的。虽然人们对炭疽毒素的结构和酶活性了解很多，但对这些毒素致病的细胞机制了解较少。目前还不清楚LF是否有其他靶点，以及LF和EF是以协同方式发挥作用，还是通过单独的机制发挥作用。 在这项资助中，我们建议使用果蝇来分析炭疽毒素LF和EF的功能。我们将重点分析新的毒素诱导的表型，并确定介导这些效应的靶点。此外，我们还将分析LF和EF之间强大的遗传协同作用的基础，以及这些毒素在成年果蝇中的相反致死和心脏干扰活性。最后，我们将与其他团队合作，确定LF和EF在脊椎动物中的作用是否相似。

DESCRIPTION (provided by applicant): Bacterial pathogens and the toxins they produce are a leading cause of disease and mortality in the developing world and can be used as agents for bioterrorism. Since the host target proteins for many of these toxins have been highly conserved during the course of evolution, model organisms such as Drosophila melanogaster provide effective tools for analyzing the molecular mechanism of toxin action and for identifying new host targets mediating their toxicity. Bacillus anthracis, the causative agent of anthrax, produces two exotoxins, Lethal factor (LF) and Edema factor (EF), which are required for bacterial pathogenicity. Although a great deal is known about the structures and enzymatic activities of anthrax toxins, much less is understood about the cellular mechanisms by which these toxins cause disease. It is also unclear whether LF has additional targets and whether LF and EF function in a concerted fashion or act via separate mechanisms. In this grant, we propose to use Drosophila to analyze the function of the anthrax LF and EF toxins. We will focus on analyzing novel toxin induced phenotypes and identifying targets mediating these effects. In addition, we will analyze the basis for strong genetic synergism between LF and EF as well as the opposing lethal and heart disrupting activities of these toxins in adult flies. Finally, we will collaborate with other groups to determine whether the LF and EF act similarly in vertebrates.