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: 10296740
• 负责人: Sumant Puri
• 金额: $ 37.64万
• 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/10296740
• 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; 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.

白色念珠菌在健康人群中以酵母菌的形式存在， 真菌感染，包括免疫受损个体和糖尿病患者的口咽念珠菌病（OPC）。 C.白念珠菌具有在其信号传导通路的帮助下将环境铁作为信号感知的能力， 作为促分裂原活化蛋白激酶（MAPK）Cek 1，调节基因表达以响应外源性铁 程度.最近的证据已经阐明了游离铁丰富的肠道和游离铁之间不同铁水平的作用。 铁消耗血液，使C.白色念珠菌之间选择一个致命的或有毒的生活方式，在这些 各自的niche。目前还不清楚口腔内铁含量的变化如何影响 OPC期间的毒性。我们的初步数据表明，铁螯合在小鼠OPC引起显着 毒力降低，而铁补充剂导致更大的真菌负荷在舌组织的 感染的老鼠我们还展示了铁是如何与包括C。白色 MAPK Cek 1调节真菌细胞壁（CW），从而影响对抗真菌药的反应（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）。的 本项目的主要目标是了解铁介导的C.白色念珠菌CW 进而影响OPC期间的感染结果。此外，在体外实验，以解决这一目标，我们 将使用我们的鼠OPC模型，并且小鼠将用铁补充或耗尽全身铁水平 补充（用右旋糖酐铁）和铁螯合（用铁螯合剂地拉罗司）。我们将 还研究了C.类人铁对秀丽隐杆线虫体内白色念珠菌的影响 疾病，以评估真菌毒力性状的健身直接在主机与不同的铁水平。我们的整体 假设是铁与各种信号传导途径沟通，以调节真菌CW，进而影响 菌丝形态发生、药物敏感性和对宿主免疫应答的敏感性。我们将测试 假设使用三个特定的目标：1）定义铁诱导的信号转导机制，调节C。白色 β-葡聚糖暴露、CW组分水平和菌丝形态发生，2）确定铁如何影响C. 小鼠OPC过程中白念珠菌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 针对C.白念珠菌在体外，在小鼠OPC，并在C.优美的这项工作将提供洞察如何 易感人群中不同的铁水平将影响C. OPC期间的白色念珠菌感染。