Therapeutic Inhibition of B. Anthracis Pathogenesis

炭疽杆菌是最常用的生物战剂。在生物恐怖分子或 生物战攻击时，炭疽杆菌孢子可能会在高浓度下散布到水中 飞沫，可能会在24-48天内进入人类呼吸道引起致命感染 几个小时。由于炭疽杆菌是生物战产业的焦点，美国人必须预料到 未来使用抵抗抗生素治疗和逃避疫苗保护性免疫的菌株 制定了疫苗接种计划。跨机构、跨学科的科学家团队 开发了中西部RCE的这项研究项目提案，以测试基因 可以被证明对炭疽病发病机制至关重要的决定因素可以 也是抗感染治疗的目标，通过防止感染的建立 或者阻碍它的发展。阿贡国家实验室的Natalia Maltsev和他的同事们利用 炭疽杆菌的基因组序列，以及关于细菌的所有其他可用信息 发病机制，用于计算识别对发病机制至关重要的基因 炭疽病。生物信息学的工作将建立一个实验层次，即基因 在炭疽杆菌基因组中将进行检查。密歇根大学菲利普·汉纳和多米尼克 芝加哥大学的Missiakas将突变炭疽杆菌的毒力基因，并分析其变异 细菌生长和孢子形成的缺陷。芝加哥大学的奥拉夫·施尼温德将 检测炭疽变种芽胞在动物体内的毒力特性 而芝加哥大学的詹姆斯·马达拉将分析孢子中的缺陷 在体外通过肠上皮细胞单层运输的能力。Andrzej Joachimiak， 阿贡国家实验室将确定B。 炭疽菌毒力因子。阿贡国家实验室的布莱恩·凯将利用噬菌体展示技术 炭疽杆菌毒力因子多肽配体的分离技术。多肽配体将是 用于筛选化学库。取代多肽配体的化合物 毒力因子将在感染的动物模型中进行测试，以确定预防 炭疽病的爆发。

Bacillus anthracis is the most frequently used biological warfare agent. During a bioterrorist or biological warfare attack, B. anthracis spores may be dispersed at high concentration into aqueous droplets, which may enter the respiratory tract of humans to cause a lethal infection within 24-48 hours. As B. anthracis is the focus of biological warfare industries, Americans must anticipate the future use of strains that resist antibiotic therapies and that evade the protective immunity of established vaccine programs. An inter-institutional and inter-disciplinary team of scientists developed this Research Project proposal of the Midwestern RCE to test whether genetic determinants that can be demonstrated to be essential for the pathogenesis of anthrax disease can also serve as targets for antiinfective therapy, by either preventing the establishment of an infection or hindering its progression. Natalia Maltsev and colleagues at Argonne National Laboratory exploit the genome sequence of B. anthracis, in addition to all other available information on bacterial pathogenesis, for the computational identification of genes that are essential for the pathogenesis of anthrax. Bioinformatic work will establish an experimental hierarchy, i.e. the order whereby genes in the B. anthracis genome will be examined. Philip Hanna, University of Michigan, and Dominique Missiakas, University of Chicago, will mutate B. anthracis virulence genes and analyze variants for defects in bacterial growth and spore formation. Olaf Schneewind, University of Chicago, will examine the virulence properties of spores generated from B. anthracis variants during animal infection, whereas James Madara, University of Chicago, will analyze spores for defects in the ability to traffic through monolayers of intestinal epithelial cells in vitro. Andrzej Joachimiak, Argonne National Laboratory, will determine the three-dimensional structure and function of B. anthracis virulence factors. Brian Kay, Argonne National Laboratory, will exploit phage-display technologies to isolate peptide ligands of B. anthracis virulence factors. The peptide ligands will be used for the screening of chemical libraries. Compounds that displace peptide ligands from virulence factors will be tested in animal models of infection for therapeutic properties in preventing the onset of anthrax.