Study of iron acquisition in Acinetobacter baumannii

鲍曼不动杆菌铁获取的研究

• 批准号: 7256786
• 负责人: Luis A Actis
• 金额: $ 30.9万
• 依托单位: MIAMI UNIVERSITY OXFORD
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256786
• 关键词: Acinetobacter baumannii; Affect; Affinity; Afghanistan; Anabolism; Animal Model; Antibiotic Resistance; Antibiotics; Bacteria; Behavior; Biochemical; Biological; Cell membrane; Cells; Chelating Agents; Clinical; Cloning; Code; Community-Acquired Infections; Condition; Development; Disease; Environment; Experimental Models; Fingerprint; Future; Gene Cluster; Genes; Genetic; Gram-Negative Bacteria; Heme; Hospitals; Human; Hygiene; Infection; Interruption; Iraq; Iron; Libraries; Mass Spectrum Analysis; Measures; Mediating; Medical; Membrane Proteins; Methods; Middle East; Military Hospitals; Molecular; Molecular Biology; Molecular Genetics; Nature; Pathogenesis; Patients; Physiological Processes; Physiology; Play; Production; Property; Protein Secretion; Proteins; Publishing; Purpose; Research; Research Personnel; Resistance profile; Respiratory Tract Infections; Role; Screening procedure; Sequence Analysis; Siderophores; Soldier; Source; System; Technology; Testing; Vertebrates; Virulence; Virulence Factors; Virulent; Work; Wound Infection; acinetobactin; base; extracellular; genetic element; in vivo; methicillin resistant Staphylococcus aureus; novel; pathogen; periplasm; programs; research study; secretion process; secretory protein; tool; trait; uptake; ward

DESCRIPTION (provided by applicant): Acinetobacter baumannii causes severe infections mainly in hospitalized patients. Lately, it has become a concern among wounded soldiers returning from the Middle East, where it has emerged as a "fresh superbug." While a large body of information exists on typing methods and the mechanisms this bacterium uses to acquire/transfer genetic traits involved in antibiotic resistance, very little is known on the molecular, genetic and biological bases of the diseases caused by this pathogen. A. baumannii expresses virulence determinants responsible for the pathogenesis of the severe infections it causes in humans. Among them must be iron acquisition functions that allow bacteria to prosper under the iron-limited conditions of vertebrate hosts. Our work and the limited information published by others showed that A. baumannii 19606 expresses the high-affinity acinetobactin-mediated iron acquisition system and heme uptake functions to grow in bacteriological media under iron-limiting conditions. Our hypothesis is that these iron acquisition functions play a role in the physiology and the virulence of this pathogen. However, some important aspects related to the acinetobactin biosynthesis and secretion processes have not been elucidated and nothing is known about heme uptake functions in this pathogen. Furthermore, the role of these iron acquisition functions have not been tested using a relevant animal model that reflects the infections it causes in humans. Therefore, the aims of this proposal are: 1) the characterization of the acinetobactin secretion process; 2) the analysis of heme uptake and utilization functions; 3) the study of a SecA auxiliary protein secretion function involved in iron acquisition; and 4) the study of the virulence role of the acinetobactin and heme transport with an animal model that mimics human respiratory infections. These studies should advance our understanding of the molecular and biological bases of bacterial iron acquisition functions, some of which are poorly characterized, and their role in the pathogenesis of respiratory infections in vertebrate hosts. Some of these studies, particularly those proposed in the last specific aim, should also give the bases for future work aimed at elucidating the effects of bacterial iron acquisition systems on the physiology of the vertebrate host using global approaches. The latter approaches should provide a more comprehensive appreciation of the host-pathogen interactions that result in severe infections in humans.

描述（由申请人提供）：鲍曼不动杆菌主要在住院患者中引起严重感染。最近，它已成为从中东返回的受伤士兵的一个担忧，在那里它已成为一种“新鲜的超级细菌”。虽然关于这种细菌用来获得/转移与抗生素耐药性有关的遗传性状的分型方法和机制存在大量信息，但对该病原体引起的疾病的分子、遗传和生物学基础知之甚少。鲍曼不动杆菌表达的毒力决定因素是其在人类中引起的严重感染的发病机制。其中必须包括铁获取功能，使细菌能够在脊椎动物宿主铁有限的条件下繁衍生息。我们的工作和其他人发表的有限信息表明，鲍曼不动杆菌 19606 表达高亲和力不动杆菌介导的铁获取系统和血红素摄取功能，可在铁限制条件下在细菌培养基中生长。我们的假设是，这些铁获取功能在该病原体的生理学和毒力中发挥作用。然而，与不动杆菌素生物合成和分泌过程相关的一些重要方面尚未阐明，并且对该病原体的血红素摄取功能一无所知。此外，这些铁获取功能的作用尚未使用反映其在人类中引起的感染的相关动物模型进行测试。因此，本提案的目的是：1）不动杆菌素分泌过程的表征； 2）血红素摄取利用功能分析； 3）参与铁获取的SecA辅助蛋白分泌功能的研究； 4) 使用模拟人类呼吸道感染的动物模型研究不动杆菌素和血红素转运的毒力作用。这些研究应增进我们对细菌铁获取功能的分子和生物学基础的理解（其中一些功能尚不清楚），以及它们在脊椎动物宿主呼吸道感染发病机制中的作用。其中一些研究，特别是最后一个具体目标中提出的研究，也应该为未来的工作奠定基础，旨在利用全球方法阐明细菌铁获取系统对脊椎动物宿主生理学的影响。后一种方法应该可以更全面地了解导致人类严重感染的宿主-病原体相互作用。