Virulence Gene Expression by Bacillus anthracis

炭疽杆菌的毒力基因表达

• 批准号: 6830287
• 负责人: THERESA M. KOEHLER
• 金额: $ 25.72万
• 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 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6830287
• 关键词: Bacillus anthracis; anthrax; anthrax toxin; bacterial genetics; beta lactamase; bioterrorism /chemical warfare; drug resistance; gene expression; laboratory mouse; microorganism culture; respiratory infections; virulence

DESCRIPTION (provided by applicant): Bacillus anthracis, a Gram-positive spore-forming soil bacterium and member of the Bacillus cereus group species, is distinguished by its ability to cause lethal anthrax disease in mammals, including humans. Well-established virulence factors unique to this organism are the anthrax toxin proteins and a poly-D-glutamic acid capsule. Findings of numerous investigators have established the structure and function of the anthrax toxins and capsule. Work in our laboratory has focused on the genetic basis for expression of the structural genes for the toxin proteins, pagA, lef, and cya, and more recently, the capsule biosynthesis operon, capBCAD. Our model for virulence gene regulation is of increasing complexity and includes numerous trans-acting regulators. The most critical and far-reaching regulator is atxA, a gene that appears to be unique to B. anthracis, atxA is essential for expression of all three toxin genes and contributes to control of the capsule operon. In experiments proposed here, we will continue our investigations of virulence gene expression by testing our current model for regulation of virulence. Our overall approach will be to determine the function of virulence gene regulators in B. anthracis cultured in vitro and to test for significance in a mouse inhalation model for anthrax. We will also assess the physiological roles of newly identified targets of established regulators. Finally, we will probe the molecular basis for differences in beta-lactamase gene expression between prototypical penicillin-susceptible and less common penicillin-resistant B. anthracis stains. Bacillus anthracis is the lead bacterium on the Select Agent List. The intentional release of spores in the fall of 2001 in the U.S. that resulted in eleven confirmed cases of anthrax and five deaths dramatically illustrated the public health threat this organism can pose when as a bioweapon. As the recent U.S. cases showed, inhalation of B. anthracis spores can result in a fatal clinical outcome in humans and only timely post-exposure intervention can limit the extent of the disease. Our overall objective is to identify and characterize B. anthracis determinants that impact B. anthracis infection in a mouse model for inhalation anthrax. Such determinants are potential targets for therapeutic intervention and/or possible components for new subunit vaccines.

描述（由申请人提供）：炭疽芽孢杆菌，一种革兰氏阳性孢子形成的土壤细菌和蜡状芽孢杆菌群的成员，其特点是其在包括人类在内的哺乳动物中引起致命性炭疽病的能力。该生物特有的良好毒力因子是炭疽毒素蛋白和多-D-谷氨酸胶囊。众多研究人员的发现已经建立了炭疽毒素和胶囊的结构和功能。我们实验室的工作集中在遗传基础上，用于表达毒素蛋白，PAGA，LEF和CYA的结构基因，以及最近的胶囊生物合成操纵子Capbcad。我们的毒力基因调节模型的复杂性增加，包括许多跨作用调节剂。最关键，最深远的调节剂是ATXA，它似乎是炭疽芽孢杆菌独有的基因，ATXA对于表达所有三种毒素基因的表达至关重要，并有助于控制胶囊操纵子。在这里提出的实验中，我们将通过测试当前的毒力调节模型来继续研究毒力基因表达。我们的总体方法是确定在体外培养的炭疽芽孢杆菌中毒力基因调节剂的功能，并在小鼠吸入模型中测试炭疽的显着性。我们还将评估已建立监管机构的新确定靶标的生理作用。 最后，我们将探究分子基础，以探测β-内酰胺酶基因表达的差异原型青霉素敏感和耐药性抗贫血链球菌b.炭疽杆菌染色的差异。炭疽芽孢杆菌是精选剂列表上的铅细菌。在2001年秋天，有意释放孢子，导致11例确认炭疽病病例，5例死亡案件大声阐明了该生物作为生物武器时可能构成的公共卫生威胁。如最近的美国病例所示，吸入炭疽芽孢杆菌孢子会导致人类致命的临床结果，并且只有及时的暴露后干预才能限制疾病的程度。我们的总体目标是识别和表征炭疽芽孢杆菌的决定因素，这些决定因素会影响小鼠模型中的炭疽芽孢杆菌感染以吸入炭疽。此类决定因素是治疗干预的潜在靶标和/或新的亚基疫苗的可能成分。