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

白色念珠菌在健康人群中以酵母菌的形式存在，但可引起粘膜和全身真菌感染， 免疫受损个体和糖尿病患者的感染。C.白色念珠菌能够感知环境 铁作为一个信号的帮助下，其信号传导途径，如丝裂原活化蛋白激酶（MAPK） Cek 1，调节基因表达对外源性铁水平的反应。最近的证据揭示了 在富含游离铁的肠道和缺乏游离铁的血液之间不同铁水平的作用，使得C.白色念珠菌 在这些各自的利基中选择一种自私或恶毒的生活方式。虽然不知道变化是否 我们的初步数据显示，口腔内的铁含量也可能影响口腔念珠菌病的毒力。 铁螯合在小鼠口腔念珠菌病中引起显著增强的毒力; 人体内的铁水平与较高的口腔C频率相关。白色念珠菌携带。这个的主要目标 目的是了解宿主铁水平在调节C.白色念珠菌我们将用我们 小鼠口腔念珠菌病模型和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）。我们的整体 假设是宿主铁水平促进口腔粘膜携带（在相对高游离铁下 条件下）或毒力（在相对低的游离铁条件下）通过影响C.白念珠菌基因表达和 宿主巨噬细胞功能。我们将使用两个具体目标来测试我们的假设：1）确定宿主铁是否 调制C.白念珠菌携带和感染水平在口腔，并确定铁依赖性的变化， 体内真菌基因表达和2）评估宿主和C.白色念珠菌铁水平 巨噬细胞的吞噬作用和随后的细胞内存活。白色念珠菌这项工作将提供 对唾液铁水平作为增强口腔黏膜免疫敏感性的标志物的潜在用途的见解 携带和口咽念珠菌病。

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.