Iron and O2 in the Regulation of P. aeruginosa Virulence

铁和 O2 在铜绿假单胞菌毒力调节中的作用

• 批准号: 7152908
• 负责人: Michael L. Vasil
• 金额: $ 48.87万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-04-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7152908
• 关键词: Aerobic; Affect; Affinity; Age; Bacteria; Binding; Biochemical Genetics; Biological; Biological Process; Biology; Cells; Characteristics; Chronic; Cleaved cell; Condition; Conflict (Psychology); Data; Endopeptidases; Environment; Escherichia; Exotoxins; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Hand; Homeostasis; Homologous Gene; Infection; Iron; Iron-Binding Proteins; Knowledge; Lactoferrin; Lung; Mediating; Microbe; Molecular Weight; Nitrogen; Nutrient; Organism; Outcome; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathogenesis; Peptide Hydrolases; Play; Population; Production; Proteins; Pseudomonas aeruginosa; Regulation; Reporting; Repressor Proteins; Role; Severities; Siderophores; Signal Transduction; Small RNA; Stress; Structure-Activity Relationship; System; Toxin; Transcript; Universities; Variant; Virulence; Virulence Factors; analog; antimicrobial drug; bacterioferritin; base; computerized data processing; cystic fibrosis patients; decorin; extracellular; macromolecule; microbial; novel; pathogen; pyoverdin; receptor; response; uptake

Pseudomonas aeruginosa is a malicious opportunistic pathogen both in terms of the severity and the outcome of infections it causes. A significant proportion of patients with cystic fibrosis (CF) is colonized at an early age (1-2yrs), and most ultimately succumbs to a chronic lung infection from P. aeruginosa. The myriad of virulence determinants, including colonization factors and toxins that P. aeruginosa produces contribute to its pathogenic potential. Unfortunately, the exact contribution of these factors, alone or in combination, to even the simplest kind of P. aeruginosa infection has not yet been elucidated. Expression of all the identified major virulence determinants in this organism is regulated by a variety of environmental conditions, which the organism encounters at some point in its journey through the host. Consequently variations in available environmental iron undoubtedly contribute to the pathogenesis of P. aeruginosa infections. Production of specific virulence factors of this organism are induced in response to limiting amounts of iron, a natural occurring environment in mammalian hosts. The dynamic control of intracellular iron concentrations is paramount to all biological systems. One aspect of this issue is that, especially in an aerobic environment, biologically useful iron (i.e. Fe2*) is extremely limiting or it is highly insoluble (i.e.Fe3*). Accordingly, biological entities have evolved efficient mechanisms to acquire this nutrient from the insoluble form, which is generally in plentiful quantities. On the other hand, further acquisition of iron above biologically useful concentrations can have dire consequences for a cell. Excess free iron will catalyze the generation of highly reactive oxygen and nitrogen intermediates that will damage all known biological macromolecules. This conflict, in a major way is dealt with in a diverse array of pathogenic and commensal prokaryotic microbes, by repressor proteins, which play the key role in controlling iron homeostasis at the level of transcription. The ferric uptake regulator (Fur) serves this function in many bacteria. In fact, in the opportunistic pathogen P. aeruginosa Fur (PA-Fur) is an essential protein that controls the expression of genes involved in the acquisition of environmental iron, including those that contribute to its virulence. This project will investigate the role of PA-Fur and PA-Fur regulated genes in the pathogenesis of P. aeruginosa infections for the ultimate goal or developing novel antimicrobial agents against this formidable opportunist.

铜绿假单胞菌在严重程度和 引起的感染结果。囊性纤维化（CF）的大部分患者被定植 年龄（1-2岁），最终最终屈服于铜绿假单胞菌的慢性肺部感染。这 无数的毒力决定因素，包括铜绿假单胞菌产生的定植因子和毒素 有助于其致病潜力。不幸的是，这些因素的确切贡献，单独或 结合，即使是最简单的铜绿假单胞菌感染，尚未阐明。表达 该生物体中所有确定的主要毒力决定因素受多种环境调节 条件，生物体在宿主的旅程中的某个时刻遇到的条件。最后 可用环境铁的变化无疑有助于铜绿假单胞菌的发病机理 感染。该生物的特定毒力因子的产生是响应限制而诱导的 哺乳动物宿主中有大量的铁，这是一种自然发生的环境。细胞内的动态控制 铁浓度对于所有生物系统至关重要。这个问题的一个方面是，尤其是 有氧环境，生物学上有用的铁（即Fe2*）极限限制或高度不溶于（即Fe3*）。 因此，生物实体已经发展了有效的机制，可以从不溶性中获取这种养分 形式，通常数量很多。另一方面，在生物学上进一步获取铁 有用的浓度可能会对细胞产生可怕的后果。多余的自由铁会催化产生 高反应性氧和氮中间会损害所有已知的生物大分子。 这种冲突以一种主要的方式处理了各种各样的致病性和共生原核生物 微生物，通过阻遏蛋白，在控制铁稳态方面起着关键作用 转录。铁摄取调节剂（Fur）在许多细菌中发挥了这一功能。实际上，在 机会性病原体铜绿假单胞菌（PA-FUR）是一种基本蛋白质，控制着表达的表达 涉及获得环境铁的基因，包括促成其毒力的基因。这 项目将研究PA-FUR和PA-FUR调节基因在铜绿假单胞菌发病机理中的作用 最终目标的感染或开发针对这种强大机会主义的新型抗菌剂。