Therapeutic Inhibition of B. Anthracis Pathogenesis

炭疽杆菌发病机制的治疗性抑制

• 批准号: 7700322
• 负责人: ANDRZEJ JOACHIMIAK
• 金额: $ 47.49万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7700322
• 关键词: American; Animal Disease Models; Animal Model; Animals; Anthrax disease; Anti-Infective Agents; Antibiotic Therapy; Bacillus anthracis; Bacillus anthracis spore; Bacillus cereus; Bioinformatics; Biological Warfare; Cavia; Chicago; Computer Simulation; Defect; Disease; Epithelial Cells; Essential Genes; Future; Genes; Genetic; Genetic Determinism; Genome; Goals; Growth; Hour; Human; Immunity; In Vitro; Industry; Infection; Intestines; Laboratories; Ligands; Michigan; Molecular; Mus; Mutate; Pathogenesis; Peptides; Phage Display; Property; Proteins; Reproduction spores; Research; Research Personnel; Research Project Grants; Respiratory System; Scientist; Screening procedure; Sequence Analysis; Structure; Technology; Testing; Therapeutic; Universities; Vaccines; Variant; Virulence; Virulence Factors; Work; aqueous; assay development; experimental analysis; genome sequencing; inhibitor/antagonist; intestinal epithelium; microbial genome; monolayer; prevent; programs; small molecule libraries; three dimensional structure; trafficking

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.

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，B.炭疽孢子可以以高浓度分散到水溶液中， 飞沫，可进入人类呼吸道，在24-48小时内引起致命感染 小时作为B。炭疽病是生物战工业的焦点，美国人必须预见到 未来使用抵抗抗生素治疗和逃避保护性免疫的菌株， 制定疫苗计划。一个跨机构和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，以测试基因是否 可以证明是炭疽病发病机理所必需的决定因素， 也可作为抗感染治疗的靶点， 或阻碍其发展。阿贡国家实验室的娜塔莉亚马尔采夫和同事利用 B的基因组序列炭疽，除了所有其他可用的信息，细菌 发病机理，用于计算鉴定发病机理所必需的基因 炭疽热生物信息学工作将建立一个实验层次，即基因的顺序， 在B。炭疽菌的基因组将被检查。密歇根大学的菲利普·汉纳和多米尼克 芝加哥大学的Missiakas将突变B。炭疽毒力基因并分析变异体 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 检查由B产生的孢子的毒力特性。动物期间的炭疽变种 而芝加哥大学的詹姆斯·马达拉将分析孢子中的缺陷， 在体外运输通过单层肠上皮细胞的能力。安杰伊·约阿希姆亚克， 阿贡国家实验室，将确定B的三维结构和功能。 炭疽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 分离B的肽配体的技术。炭疽毒力因子肽配体将是 用于筛选化学文库。取代肽配体的化合物， 将在动物感染模型中测试毒力因子的治疗特性， 炭疽病的爆发