Virulence Gene Expression by Bacillus anthracis

炭疽杆菌的毒力基因表达

• 批准号: 8683058
• 负责人: THERESA M. KOEHLER
• 金额: $ 29.55万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8683058
• 关键词: Affect; Amino Acid Sequence; Amino Acid Substitution; Animals; Anthrax disease; Attenuated; Bacillus (bacterium); Bacillus anthracis; Bacillus anthracis spore; Bacteria; Bacterial Physiology; Bicarbonate Ion; Bicarbonate Ions; Binding; Biochemical; Breathing; Carbohydrates; Categories; Cell Cycle; Cells; Cessation of life; Code; Cutaneous; DNA Binding; DNA Sequence; DNA-Directed RNA Polymerase; Data; Development; Diagnostic; Dose; Elements; Environment; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Germination; Growth; Histopathology; Homologous Gene; Housekeeping; Infection; Infectious Agent; Investigation; Knowledge; Laboratories; Link; Measurement; Modeling; Modification; Molecular; Monitor; Mus; Nature; Operon; Parents; Pathogenesis; Phase; Physiological; Post-Translational Protein Processing; Process; Proteins; Regulator Genes; Regulon; Reproduction spores; Route; Sigma Factor; Signal Transduction; Structural Genes; Time; Tissues; Toxin; Vaccines; Virulence; Virulence Factors; Work; anthrax toxin; base; capsule; gain of function; gastrointestinal; interest; member; mutant; novel; pathogen; promoter; public health relevance; response

DESCRIPTION (provided by applicant): This proposal focuses on Bacillus anthracis virulence gene control, with emphasis on the expression and function of the major virulence gene regulator AtxA. B. anthracis is a developmental bacterium existing in two distinct physiological states, metabolically active vegetative cells and dormant spores. The spore - vegetative cell cycle is of fundamental importance in pathogenesis. Spores enter a mammalian host and germinate to become vegetative cells. During infection, B. anthracis remains vegetative and synthesizes capsule, anthrax toxin proteins, and other factors that facilitate pathogenesis; sporulation does not occur. However, upon death of the host when vegetative cells are exposed to the environment, toxins and capsule are not produced and B. anthracis sporulates efficiently. Thus, the inverse relationship between virulence factor synthesis and sporulation is physiologically significant for anthrax pathogenesis. The major link between these two processes is AtxA. Investigations in our laboratory and others have revealed a relationship between this major pleiotropic regulator of virulence gene expression and the physiological state of cells grown in batch culture. B. anthracis homologues of developmental regulators that have been well-characterized in the non- pathogenic Bacillus species B. subtilis have been linked to transcription of atxA. Moreover, AtxA function appears to be controlled by post-translational modification and host-associated signals. In this work, we will (1) perform functional analyses of AtxA, (2) determine molecular mechanisms for control of atxA expression, and (3) establish the physiological relevance of atxA regulators and specific functional modifications of the AtxA protein in anthrax disease. B. anthracis is a Category A Select Agent and the development of more effective chemotherapeutics, vaccines, and diagnostics for anthrax disease is a national priority. Defining and characterizing the molecular mechanisms by which B. anthracis controls virulence gene expression will advance our fundamental understanding of B. anthracis pathogenesis and facilitate a rational approach for the development of anthrax countermeasures. Furthermore, information regarding the molecular function of the novel regulator AtxA will contribute to our overall understanding of mechanisms of gene regulation. Finally, information obtained in this study can be applied to other infectious agents because B. anthracis is an ideal model for multiple features of host-pathogen interactions, environmental signaling in bacteria, and other aspects of bacterial physiology.

描述（由申请人提供）：该提案的重点是炭疽杆菌毒力基因控制，重点是主要毒力基因调节剂ATXA的表达和功能。 B.炭疽病是在两个不同的生理状态，代谢活性的营养细胞和休眠孢子中存在的发育细菌。孢子 - 营养细胞周期在发病机理中至关重要。孢子进入哺乳动物宿主并发芽成为营养细胞。在感染期间，炭疽芽孢杆菌保持营养，并合成胶囊，炭疽毒素蛋白以及其他促进发病机理的因素。孢子不会发生。但是，宿主死亡后，当营养细胞暴露于环境时，毒素和胶囊不会产生，炭疽芽孢杆菌会有效地孢子。因此，毒力因子合成与孢子形成之间的反比关系对于炭疽发病机理具有生理意义。这两个过程之间的主要链接是ATXA。我们实验室和其他人的研究揭示了这种毒力基因表达的主要多效性调节剂与在批处理培养中生长的细胞生理状态之间的关系。 B.在非致病性芽孢杆菌物种中已经充分表征的发育调节剂的炭疽病同源物B.枯草菌与ATXA的转录有关。此外，ATXA功能似乎通过翻译后修改和与主机相关的信号控制。在这项工作中，我们将（1）对ATXA进行功能分析，（2）确定控制ATXA表达的分子机制，（3）建立ATXA调节剂的生理相关性和ATXA蛋白在ANTHAX疾病中的特定功能修饰。 B.炭疽病是选择剂的类别，并且开发了更有效的化学治疗剂，疫苗和炭疽病诊断药是国家的优先事项。定义和表征分子机制，炭疽芽孢杆菌控制毒力基因表达将提高我们对炭疽芽孢杆菌发病机理的基本理解，并促进一种理性的方法来发展炭疽对立。此外，有关新调节剂ATXA的分子功能的信息将有助于我们对基因调节机制的整体理解。最后，本研究获得的信息可以应用于其他传染剂，因为炭疽芽孢杆菌是宿主 - 病原体相互作用，细菌中的环境信号传导以及细菌生理学的其他方面的多个特征的理想模型。