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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

基本信息

批准号：
10647656
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
项目类别：
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

项目摘要

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中以共生酵母菌的形式存在，但它可引起粘膜和全身真菌感染，包括免疫功能低下的个人和糖尿病患者的口咽念珠菌病(OPC)。白念珠菌有能力通过其信号通路感知环境中的铁作为信号，如作为丝裂原活化蛋白激酶(MAPK)的CEK1，调节基因表达对外源铁的响应级别。最近的证据已经阐明了不同的铁水平在富含游离铁的肠道和游离铁之间的作用铁会消耗血液，使白色念珠菌能够在共生或有毒的生活方式中做出选择各自的利基市场。口腔内铁水平的变化将如何影响口腔目前尚不清楚。 OPC期间的毒力。我们的初步数据显示，铁在小鼠OPC中的螯合作用导致显著毒力降低，而补铁导致舌组织中更多的真菌负荷受感染的小鼠。我们还展示了铁是如何与包括白色念珠菌在内的各种信号通路进行交流的。 MAPK CEK1调节真菌细胞壁(CW)，从而影响对抗真菌药物的反应(通过改变CW 成分水平)和宿主免疫攻击(通过影响免疫原性β-葡聚糖在CW中的暴露)。这个该项目的主要目标是了解铁介导的白色念珠菌Cw变化背后的机制。这反过来又影响OPC期间感染的结果。此外，为了达到这一目标，我们进行了体外实验将使用我们的小鼠OPC模型，小鼠将通过铁补充或耗尽全身铁水平分别补充(右旋糖酐铁)和铁螯合(铁螯合剂去铁西罗)。我们会用类人铁研究白色念珠菌在秀丽线虫体内的粘膜定植在不同铁水平的寄主中，直接评估真菌毒力性状的适合性。我们的整体假说认为，铁与不同的信号通路沟通，以调节真菌CW，进而影响 OPC的菌丝形态发生、药物敏感性和对宿主免疫反应的敏感性。我们将测试我们的假设使用三个特定的目的：1)定义铁诱导的信号机制，调节白色念珠菌 β-葡聚糖暴露、CW组分水平和菌丝形态发生，2)决定了铁如何影响C。白念珠菌Cw重塑和菌丝形态发生在OPC中对抗真菌药物的影响敏感性，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、在小鼠OPC期间和在线虫体内抗白色念珠菌。这项工作将提供关于如何易感人群铁水平的变化将影响OPC期间白色念珠菌感染的结局。