Virulence Gene Expression by Bacillus anthracis

描述（由申请人提供）：炭疽芽孢杆菌是一种革兰氏阳性孢子形成土壤细菌，属于蜡样芽孢杆菌属，其特征在于能够在哺乳动物（包括人类）中引起致死性炭疽病。这种微生物特有的公认毒力因子是炭疽毒素蛋白和聚D-谷氨酸荚膜。许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。我们实验室的工作主要集中在毒素蛋白pagA、lef和cya的结构基因表达的遗传基础上，最近还研究了荚膜生物合成操纵子capBCAD。我们的毒力基因调控模型越来越复杂，包括许多反式作用的监管机构。最关键和影响最深远的调节因子是atxA，这是一种似乎是B所独有的基因。在炭疽杆菌中，atxA是所有三种毒素基因表达所必需的，并有助于控制荚膜操纵子。在这里提出的实验中，我们将通过测试我们目前的毒力调控模型来继续我们对毒力基因表达的研究。我们的总体方法将是确定B中毒力基因调节子的功能。在体外培养的炭疽菌，并测试在小鼠吸入模型中的显着性炭疽。我们还将评估新确定的既定监管机构的目标的生理作用。 最后，我们将探讨典型青霉素敏感和不常见青霉素耐药B之间β-内酰胺酶基因表达差异的分子基础。炭疽菌染色。炭疽杆菌是选择性病原体清单上的主要细菌。2001年秋天在美国故意释放孢子，导致11例确诊的炭疽病例和5例死亡，戏剧性地说明了这种生物作为生物武器可能造成的公共卫生威胁。正如美国最近的病例所显示的那样，吸入B。炭疽孢子可对人类造成致命的临床后果，只有及时进行接触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B。影响B的炭疽决定因素。小鼠吸入性炭疽模型中的炭疽感染。这些决定因素是治疗干预的潜在靶点和/或新亚单位疫苗的可能组分。

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.