Study of iron acquisition in Acinetobacter baumannii

描述(申请人提供)：鲍曼不动杆菌可引起严重感染，主要发生在住院患者。最近，它已经成为从中东归来的受伤士兵的担忧，在那里，它已经成为一种“新的超级细菌”。虽然有大量关于分型方法和这种细菌用来获得/转移与抗生素耐药性有关的遗传特征的机制的信息，但对这种病原体引起的疾病的分子、遗传和生物学基础知之甚少。鲍曼不动杆菌表达毒力决定因素，这些决定因素对它在人类中引起的严重感染的发病机制负责。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表达高亲和力的Acinetobactin介导的铁获取系统和血红素吸收功能，在限制铁的细菌培养基中生长。我们的假设是，这些铁获取功能在这种病原体的生理和毒力中发挥了作用。然而，与腺泡刺激素的生物合成和分泌过程相关的一些重要方面尚未阐明，对该病原体中的血红素摄取功能也一无所知。此外，这些铁获取功能的作用还没有通过相关的动物模型进行测试，这些动物模型反映了它对人类造成的感染。因此，这项建议的目的是：1)表征腺泡结合蛋白的分泌过程；2)分析血红素的吸收和利用功能；3)研究参与铁获取的SECA辅助蛋白分泌功能；4)利用模拟人类呼吸道感染的动物模型研究腺泡结合蛋白和血红素运输的毒力作用。这些研究将促进我们对细菌铁获取功能的分子和生物学基础的理解，以及它们在脊椎动物呼吸道感染发病机制中的作用。其中一些研究，特别是上一个具体目标中提出的研究，也应该为今后的工作奠定基础，这些工作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的影响。后一种方法应该对导致人类严重感染的宿主-病原体相互作用提供更全面的评价。

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.