The role of pH and iron in co-regulating replication and expression of virulence factors in Coxiella burnetii

pH 值和铁在共同调节伯氏柯克斯体毒力因子复制和表达中的作用

• 批准号: 9911243
• 负责人: Savannah Elizabeth Sanchez
• 金额: $ 3.86万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-16 至 2022-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911243
• 关键词: Acids; Acute; Address; Bacteria; Biogenesis; Carrier Proteins; Cells; Characteristics; Coxiella; Coxiella burnetii; Disease; Endocarditis; Endocytosis; Escherichia coli; Etiology; Eukaryotic Cell; Exhibits; Fever; Genes; Genetic Transcription; Genome; Growth; Hepatitis; Human; Infection; Iron; Legionella pneumophila; Life; Liquid substance; Liver; Macronutrients Nutrition; Metabolic; Metabolism; Micronutrients; Modeling; Molecular; Neisseria gonorrhoeae; Nutrient; Nutritional Requirements; Organ; Pathogenesis; Phagocytes; Phagolysosome; Phase; Phylogenetic Analysis; Physiological; Production; Protein Biosynthesis; Proteins; Recycling; Regulation; Reporting; Role; Sequence Analysis; Siderophores; Source; Splenic Red Pulp; Starvation; Stress; System; TFRC gene; Testing; Transferrin; Tropism; Type IV Secretion System Pathway; Vacuole; Virulence; Virulence Factors; Yersinia enterocolitica; acid stress; cell type; design; extracellular; human disease; pathogen; pathogen genome; pathogenic bacteria; protein expression; receptor expression; response; stress tolerance; tissue tropism; transcription factor; uptake

7. Project Summary/Abstract Coxiella burnetii, the causative agent of Query (Q) fever in humans and coxiellosis in other species is a highly infectious obligate intracellular bacterium. In humans, this disease is largely self-limiting, presenting as an acute febrile disease; however, the pathogen is capable of causing both hepatitis and potentially life- threatening endocarditis. C. burnetii is capable of infecting a broad range of eukaryotic cell types within which the bacterium replicates exclusively in a host-derived compartment referred to as the Coxiella Containing Vacuole (CCV). CCV biogenesis is dependent on C. burnetii secretion of Type IV secretion system (T4SS) effector molecules and in their absence the bacterium is unable to replicate intracellularly and/or exhibit virulence. Studies on the physicochemical requirements of C. burnetii have established that the moderately acidic pH of the CCV, a phagolysosome-like vacuole, dictates C. burnetii nutrient transport, protein synthesis and replication. Additionally, C. burnetii exhibits tropism for tissues directly involved in iron storage and recycling (e.g., the liver and splenic red pulp). High iron loads in the liver and splenic red pulp, and known uptake of extracellular material into the CCV lumen by fluid phase endocytosis, is consistent with uptake of iron-containing molecules (e.g., transferrin) into the CCV. Cultured host cells infected with C. burnetii have been shown to increase expression of transferrin receptors, suggesting a demand for iron, a micronutrient previously reported to have a limited role in C. burnetii pathogenesis. While genome sequence analysis suggests C. burnetii has a limited capacity to acquire iron via siderophores or uptake systems for iron- containing molecules, the C. burnetii genome does encode the ferrous iron uptake transporter FeoAB suggesting that molecular iron is the natural iron source for C. burnetii. Additionally, the C. burnetii genome encodes the transcriptional regulator stringent starvation protein A (SspA) that in Escherichia coli has been shown to positively regulate genes involved in acid tolerance. Since replication is essential for virulence, and replication is dependent on both moderately acidic pH and iron, we hypothesize that pathogen replication is triggered by simultaneous sensing of niche-specific variables (i.e., acidic pH and iron) that co-regulate expression of virulence factors required for CCV biogenesis and pathogen growth.

7.项目总结/摘要 贝氏柯克斯体（Coxiellaburnetii）是引起人类Q热和其他物种的柯克斯体病的病原体， 传染性专性细胞内细菌。在人类中，这种疾病在很大程度上是自限性的， 急性发热性疾病;然而，病原体能够引起肝炎和潜在的生命， 有心内膜炎的危险C.贝氏体能够感染广泛的真核细胞类型， 细菌仅在宿主衍生的隔室中复制，所述隔室被称为含有Coxiella的隔室。 胆固醇（CCV）。CCV的生物发生依赖于C.贝氏IV型分泌系统 效应分子，并且在它们不存在的情况下，细菌不能在细胞内复制和/或表现出 毒性研究了香蜂草的理化要求。Burnetii已经确定， CCV的酸性pH，一个吞噬溶酶体样的空泡，决定了C。贝氏营养物质转运，蛋白质合成 和复制。此外，C.伯内特氏菌表现出对直接参与铁储存的组织的嗜性， 回收（例如，肝和脾红髓）。肝脏和脾脏红髓中的铁负荷很高，并且已知 通过液相内吞作用将细胞外物质摄取到CCV腔中，与 含铁分子（例如，转铁蛋白）进入CCV。用C.伯内特湖 已被证明增加转铁蛋白受体的表达，这表明对铁，一种微量营养素的需求 以前报道在C.贝氏菌致病机理而基因组序列分析 C.伯内特虫通过铁载体或铁吸收系统获得铁的能力有限， 含有分子，C.贝氏体基因组编码亚铁吸收转运蛋白FeoAB 表明分子铁是C.伯内特氏菌此外，C.贝氏体基因组 编码转录调节因子严格饥饿蛋白A（SspA），在大肠杆菌中， 显示出积极调节与耐酸性有关的基因。由于复制对毒力至关重要， 复制依赖于中等酸性的pH值和铁，我们假设病原体复制是 通过同时感测特定于小生境的变量（即，酸性pH值和铁），共同调节 CCV生物发生和病原体生长所需的毒力因子的表达。