Nutrient Uptake during Anthrax Disease

项目摘要 病原菌需要获得必需的营养物质，以建立和维持其体内的感染。 hosts.宿主限制了对这些营养素的获取，这一概念称为营养免疫。因此，在本发明中， 细菌营养输入系统，以及控制它们的代谢调节剂，代表了下一个- 新型抗菌剂的产生目标。革兰氏阳性菌B。炭疽病是导致 炭疽病病原体和生物恐怖主义武器。这种病原体具有非凡的能力， 在脊椎动物中复制，这一优点有助于研究细菌如何克服营养 免疫力众所周知， 支链氨基酸生物合成的倒数第二步， 是所有生命所必需的，需要一种酶，其活性取决于铁硫簇。 我们 已发表的工作和初步数据表明，B。炭疽菌和相关物种利用一种聪明的 控制支链氨基酸摄入量与代谢平衡的代谢机制 在复杂的宿主环境中维持铁稳态。工作的前提是， 当外部铁水平低时，芽孢杆菌是缬氨酸的营养缺陷型，因此不能使分枝杆菌产生分枝。 氨基酸，我们假设宿主从血液蛋白中释放的缬氨酸刺激铁的获得 通过革兰氏阳性菌中的毒力全局调节因子CodY。这反过来又促进了进口 铁，从而缓解营养缺陷型和燃料在宿主血液和组织中的快速复制。在Aim中 在本项目的第1部分中，我们发现了一种新的支链氨基酸转运蛋白，并对其进行了表征。 其在血红素铁获得的CodY依赖性刺激中的作用。在目标2中，我们研究了 通过两种新发现的血红素结合酶从血红素中释放铁的机制。 最后，在目标3中，我们整合了中心模型的关键方面，以确定这些方面的重要性。 系统在炭疽病期间发展芽孢杆菌感染的每一步中。由于这一网络 营养吸收系统和调节剂在几个临床上重要的物种中也有同系物， 在这里的工作将提供病原菌如何燃料他们的代谢过程中的基本知识 毒性

Project Summary Pathogenic bacteria need to acquire essential nutrients to establish and sustain an infection in their hosts. The host restricts access to such nutrients, a concept termed nutritional immunity. As such, bacterial nutrient import systems, and the metabolic regulators that govern them, represent next- generation targets for novel antimicrobials. The Gram-positive bacterium B. anthracis is the causative agent of anthrax disease and a weapon of bioterrorism. This pathogen has a remarkable ability to replicate in vertebrates, a virtue that is useful for the study of how bacteria overcome nutritional immunity. It is well known that the penultimate step in the biosynthesis of branched amino acids, which are necessary for all life, requires an enzyme whose activity is dependent on an iron-sulfur cluster. Our published work and preliminary data suggests that B. anthracis and related species employ a clever metabolic mechanism to govern the balance between the intake of branched amino acids and the maintenance of iron homeostasis in complex host environments. Working under the premise that bacillus is auxotrophic for valine when external iron levels are low, and thus cannot make branched amino acids, we hypothesize that host valine liberated from blood proteins stimulates iron acquisition via the global regulator of virulence in Gram-positive bacteria, CodY. This in turn promotes the import of iron, thereby relieving the auxotrophy and fueling rapid replication in host blood and tissues. In Aim 1 of this project, we report the discovery of a novel branched amino acid transporter and characterize its role in the CodY-dependent stimulation of heme-iron acquisition. In Aim 2, we investigate the mechanism of iron release from heme via two newly uncovered heme-binding enzymes in bacillus. Finally, in Aim 3, we integrate key aspects of the central model to determine the importance of these systems in every step of a developing bacillus infection during anthrax disease. Since this network of nutrient uptake systems and regulators also have homologs in several clinically significant species, the work here will provide fundamental knowledge of how pathogenic bacteria fuel their metabolism during virulence.