Role of host iron in C. albicans oral commensal carriage and oropharyngeal candidiasis

宿主铁在白色念珠菌口腔共生携带和口咽念珠菌病中的作用

• 批准号: 9220979
• 负责人: Sumant Puri
• 金额: $ 11.89万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220979
• 关键词: Address; Affect; Antibiotics; Blood; Candida albicans; Cell surface; Cell-Cell Adhesion; Cells; Chromatin; Data; Disease; Exhibits; Foundations; Frequencies; Fungal Genes; Gene Expression; Genes; Goals; Growth; Human; Immune System Diseases; Immune System and Related Disorders; Immunocompromised Host; Immunosuppression; In Vitro; Incidence; Individual; Infection; Infiltration; Inflammatory; Iron; Iron Chelating Agents; Iron Chelation; Iron Overload; Iron-Dextran Complex; Knowledge; Life Style; Light; Link; Measures; Mediating; Mitogen-Activated Protein Kinases; Modeling; Morbidity - disease rate; Mus; Mycoses; Oral; Oral candidiasis; Oral cavity; Organism; Pathogenicity; Pattern; Phagocytes; Phagocytosis; Phosphorylation; Play; Predisposition; Role; Salivary; Signal Pathway; Signal Transduction; Surface Properties; Symbiosis; Testing; Time; Tissues; Tongue; Variant; Virulence; Virulent; Work; Yeasts; beta-Glucans; diabetic; fungus; in vivo; indexing; insight; iron supplementation; macrophage; microbial; mortality; novel; oral cavity epithelium; oral commensal; oropharyngeal thrush; pathogen; permissiveness; response; trait; uptake

Candida albicans exists as commensal yeast in healthy people while it can cause mucosal and systemic fungal infections in immunocompromised individuals and diabetics. C. albicans has the ability to sense environmental iron as a signal with the help of its signaling pathways, such as Mitogen Activated Protein Kinase (MAPK) Cek1, to modulate gene expression in response to extrinsic iron levels. Recent evidence has shed light on the role of different iron levels between free iron rich gut and free iron deplete blood, allowing C. albicans to choose between a commensal or virulent lifestyle in these respective niches. While it is not known if variation in iron within the oral cavity might also influence virulence during oral candidiasis, our preliminary data shows that iron chelation in murine oral candidiasis causes significantly enhanced virulence; and that higher salivary iron levels in humans correlate with a higher frequency of oral C. albicans carriage. The main goal of this project is to understand the role of host iron levels in modulating the oral growth of C. albicans. We will use our murine oral candidiasis model and mice will be repleted or depleted in systemic iron levels with iron supplementation (with iron dextran) and iron chelation (with iron chelator Deferasirox), respectively. Our overall hypothesis is that host iron levels either promote oral commensal carriage (under relative high free iron conditions) or virulence (under relative low free iron conditions) by influencing C. albicans gene expression and host macrophage function. We will test our hypothesis using two specific aims: 1) Determine whether host iron modulates C. albicans carriage and infection levels in the oral cavity, and identify iron-dependent changes in in vivo fungal gene expression and 2) Evaluate the effect of changes in host and C. albicans iron levels on phagocytosis by macrophages and subsequent intracellular survival of C. albicans. This work will provide insights into the potential use of salivary iron levels as a marker for susceptibility to enhanced oral Candidal carriage and oropharyngeal candidiasis.

白色念珠菌在健康人体内以共生酵母菌的形式存在，但可引起粘膜和全身真菌 免疫功能受损的个人和糖尿病患者的感染。白念珠菌具有感知环境的能力 铁作为一种信号，通过其信号通路，如丝裂原活化蛋白激酶(MAPK) CEK1，调节基因表达以响应外源铁水平。最近的证据揭示了 不同铁水平在游离富铁肠道和游离铁耗竭血液中的作用，使白色念珠菌 在这些各自的利基市场中，在共生或有害的生活方式之间做出选择。虽然目前还不知道是否存在变异 我们的初步数据显示，口腔内的铁也可能影响口腔念珠菌病的毒力。 小鼠口腔念珠菌病中的铁螯合作用可显著增强其毒力；唾液中的铁离子含量较高 人类体内的铁水平与口腔携带白念珠菌的频率较高相关。这样做的主要目标是 该项目旨在了解宿主铁水平在调节白色念珠菌口腔生长中的作用。我们将使用我们的 小鼠口腔念珠菌病模型和小鼠全身铁水平将被铁补充或消耗 分别补充(右旋糖酐铁)和铁螯合(铁螯合剂去铁西罗)。我们的整体 假说是，宿主铁水平要么促进口腔共生运输(在相对较高的游离铁下 条件)或毒力(在相对较低的游离铁条件下)通过影响白色念珠菌的基因表达和 宿主巨噬细胞功能。我们将使用两个特定的目标来验证我们的假设：1)确定宿主铁 调节口腔中白色念珠菌的携带和感染水平，并确定体内铁依赖的变化 活体真菌基因表达和2)评估宿主和白色念珠菌铁水平的变化对 巨噬细胞的吞噬作用和随后白念珠菌的细胞内生存。这项工作将提供 唾液铁水平作为口腔念珠菌易感性标志物的潜在应用 携带和口咽部念珠菌病。