Role of environmental iron in Candida albicans cell wall remodeling and its effect on host-pathogen interaction during oropharyngeal candidiasis

环境铁在口咽念珠菌病期间白色念珠菌细胞壁重塑中的作用及其对宿主-病原体相互作用的影响

• 批准号: 10434161
• 负责人: Sumant Puri
• 金额: $ 37.27万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434161
• 关键词: Address; Affect; Antifungal Agents; Architecture; Blood; Caenorhabditis elegans; Candida; Candida albicans; Candida auris; Cell Wall; Cells; Cellular Immunity; Chitin; Chromatin; Data; Defense Mechanisms; Drug resistance; Environment; Gene Expression; Genes; Glucans; Goals; Growth; Homeostasis; Human; Hyphae; Immune; Immune response; Immune system; Immunocompromised Host; In Vitro; Individual; Infection; Iron; Iron Chelating Agents; Iron Chelation; Iron Metabolism Disorders; Iron-Dextran Complex; Life Style; Light; Link; Mannans; Masks; Measures; Mediating; Microbial Biofilms; Mitogen-Activated Protein Kinases; Modeling; Morbidity - disease rate; Morphogenesis; Mucous Membrane; Mus; Mycoses; Nutritional Immunity; Oral; Oral candidiasis; Oral cavity; Outcome; Pathogenesis; Pattern; Persons; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Play; Population; Predisposition; Production; Property; Role; SLC11A2 gene; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Structure; Testing; Tissues; Tongue; Transcription Repressor; Transcriptional Regulation; Translations; Variant; Virulence; Virulent; Work; Yeasts; antimicrobial; beta-Glucans; cytokine; diabetic; drug sensitivity; experimental study; extracellular; fitness; fungus; immunogenic; in vivo; innate immune mechanisms; insight; iron supplementation; macrophage; microbial colonization; mortality; neutrophil; novel; oropharyngeal thrush; pathogen; recruit; response; synergism; trait; treatment strategy

Candida albicans exists as a commensal yeast in healthy people while it can cause mucosal and systemic fungal infections including oropharyngeal candidiasis (OPC) 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. Nothing is known about how variations in iron levels within the oral cavity will influence virulence during OPC. Our preliminary data shows that iron chelation in murine OPC causes significant reduction in virulence, while iron supplementation leads to greater fungal load in the tongue tissue of the infected mice. We also show how iron communicated with various signaling pathways including C. albicans MAPK Cek1 to modulate the fungal cell wall (CW), thereby affecting response to antifungals (by changing CW component levels) and host immune attack (by affecting exposure of immunogenic β-glucan in the CW). The main goal of this project is to understand the mechanisms behind iron-mediated changes in C. albicans CW that in turn effect the outcome of infection during OPC. Besides, in vitro experiments to address this goal, we will use our murine OPC 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. We will also study mucosal colonization by C. albicans in Caenorhabditis elegans worms with human-like iron disorders, to evaluate fitness of fungal virulence traits directly in host with varying iron levels. Our overall hypothesis is that iron communicates with various signaling pathways to modulate fungal CW, in turn affecting hyphal morphogenesis, drug sensitivity, and susceptibility to host immune response, in OPC. We will test our hypothesis using three specific aims: 1) Define iron-induced signaling mechanisms that modulate C. albicans β-glucan exposure, levels of CW components, and hyphal morphogenesis, 2) Determine how iron affects C. albicans CW remodeling and hyphal morphogenesis during murine OPC to impact antifungal drug susceptibility, and 3) Evaluate how changes in host iron levels modulate innate immune defense mechanisms against C. albicans in vitro, during murine OPC, and in C. elegans. This work will provide insights into how varying iron levels in susceptible populations will affect the outcome of C. albicans infection during OPC.

白色念珠菌作为健康人体内的共生酵母存在，同时可引起粘膜和全身性疾病 真菌感染，包括免疫功能低下者和糖尿病患者的口咽念珠菌病 (OPC)。 白色念珠菌能够借助其信号通路将环境铁信号感知为信号，例如 作为丝裂原激活蛋白激酶 (MAPK) Cek1，调节基因表达以响应外来铁 水平。最近的证据揭示了富含游离铁的肠道和游离铁之间不同铁水平的作用。 铁会消耗血液，使白色念珠菌能够在这些环境中选择共生或有毒的生活方式 各自的利基。目前尚不清楚口腔内铁含量的变化会如何影响 OPC期间的毒力。我们的初步数据表明，小鼠 OPC 中的铁螯合会导致显着的 毒力降低，而补充铁会导致舌头组织中的真菌负荷增加 被感染的老鼠。我们还展示了铁如何与包括白色念珠菌在内的各种信号通路进行通讯 MAPK Cek1 调节真菌细胞壁 (CW)，从而影响抗真菌药物的反应（通过改变 CW） 成分水平）和宿主免疫攻击（通过影响 CW 中免疫原性 β-葡聚糖的暴露）。这 该项目的主要目标是了解白色念珠菌 CW 中铁介导的变化背后的机制 进而影响 OPC 期间的感染结果。此外，为了实现这一目标，我们进行了体外实验 将使用我们的小鼠 OPC 模型，并且小鼠将通过铁补充或耗尽全身铁水平 分别补充（用右旋糖酐铁）和铁螯合（用铁螯合剂地拉罗司）。我们将 还用类人铁研究白色念珠菌在秀丽隐杆线虫中的粘膜定植 疾病，直接评估具有不同铁水平的宿主中真菌毒力特征的适应性。我们的整体 假设是铁与各种信号通路通讯以调节真菌 CW，进而影响 OPC 中的菌丝形态发生、药物敏感性和对宿主免疫反应的易感性。我们将测试我们的 使用三个具体目标的假设：1）定义调节白色念珠菌的铁诱导信号传导机制 β-葡聚糖暴露、CW 成分水平和菌丝形态发生，2) 确定铁如何影响 C. 小鼠 OPC 期间白色念珠菌 CW 重塑和菌丝形态发生对抗真菌药物的影响 易感性，以及 3) 评估宿主铁水平的变化如何调节先天免疫防御机制 在体外、小鼠 OPC 期间和秀丽隐杆线虫中对抗白色念珠菌。这项工作将提供有关如何 易感人群中不同的铁水平将影响 OPC 期间白色念珠菌感染的结果。