C. albicans invasion and proliferation during oral infection

摘要 口咽部念珠菌病(OPC)在众多不同的人群中引起显著的发病率，尤其是 因艾滋病、中性粒细胞减少症、糖尿病或使用类固醇而免疫功能受损的患者。在……里面 事实上，据估计，每年发生近1000万与艾滋病毒/艾滋病相关的OPC病例，近五分之一 这些人中有食道受累。唑类抗真菌药是目前治疗的主流药物 对于OPC。然而，由于出现了唑类耐药性，开发新的策略来应对 预防和治疗OPC。 我们的研究集中在这样一种假设上，即促进白念珠菌黏附和入侵的基因 上皮细胞的数量是有机体引起OPC的关键。这一假设是基于这样一个事实，即入侵 OPC患者的活组织标本揭示了有机体 在口腔上皮细胞内。黏附/侵袭功能是由与之相互作用的细胞表面蛋白执行的 宿主细胞上的同源受体。这些相互作用使有机体能够入侵口腔上皮细胞并避免 被吞噬细胞杀死。我们的数据表明，有两条黏附/侵袭途径在 OPC。途径I包括白色念珠菌表面蛋白Als3和Ssa1，它们与上皮细胞相互作用 表面蛋白表皮生长因子受体(EGFR)和HER2。途径II在我们的 初步结果。途径II包括白念珠菌表面蛋白Hyr1，它与c-Met受体结合 口腔上皮细胞和中性粒细胞上的酪氨酸激酶。我们的总体前提是路径I和路径I 途径II通过E-钙粘附素促进口腔上皮细胞对白色念珠菌的内吞作用。途径II也 白念珠菌与中性粒细胞相互作用抑制中性粒细胞杀伤的功能。 拟议研究的目标是测试路径II的功能及其机制基础，并 定义途径I和途径II之间的关系。我们将1)确定Hyr1-c-Met的作用 抑制中性粒细胞杀菌活性与上皮细胞侵袭的相互作用；2)确定 Hyr1与细胞表面侵袭素Als3和Ssa1在体外和体内的关系；3)定义了 在OPC过程中起作用的途径I和II基因。这项研究的结果将为我们提供对 白念珠菌侵袭口腔上皮细胞并下调中性粒细胞杀菌作用的机制 机械装置。这些数据不仅将提供对OPC发病机制的更深层次的理解，而且它们 也有希望确定新的潜在药物和疫苗靶点。

Abstract Oropharyngeal candidiasis (OPC) causes significant morbidity in a large, diverse population, especially patients who are immunocompromised due to AIDS, neutropenia, diabetes mellitus, or the use of steroids. In fact, it is estimated that nearly 10 million cases of HIV/AIDS-associated OPC occur annually, and nearly a fifth of these individuals have esophageal involvement. Azole antifungal agents are the current mainstay of therapy for OPC. However, because of the emergence of azole resistance, it is critical to develop novel strategies to prevent and treat OPC. Our studies have focused on the hypothesis that C. albicans genes that promote adherence to and invasion of epithelial cells are critical for the organism to cause OPC. This hypothesis is based on the fact that invasion of the superficial epithelium occurs during OPC, and that biopsy specimens from OPC patients reveal organisms within oral epithelial cells. Adherence/invasion functions are carried out by cell surface proteins that interact with cognate receptors on host cells. These interactions enable the organism to invade oral epithelial cells and avoid being killed by phagocytes. Our data indicate that there are two adherence/invasion pathways that function in OPC. Pathway I includes the C. albicans surface proteins Als3 and Ssa1, which interact with the epithelial cell surface proteins epidermal growth factor receptor (EGFR) and HER2. Pathway II is newly described in our preliminary results. Pathway II includes the C. albicans surface protein Hyr1, which binds to the c-Met receptor tyrosine kinase on both oral epithelial cells and neutrophils. Our overall premise is that both Pathway I and Pathway II promote endocytosis of C. albicans by oral epithelial cells through E-cadherin. Pathway II also functions when C. albicans interacts with neutrophils to inhibit neutrophil killing. The objectives of the proposed studies are to test Pathway II function and its mechanistic basis, and to define the relationships between Pathway I and Pathway II. We will 1) determine the role of the Hyr1-c-Met interaction in inhibition of neutrophil fungicidal activity and epithelial cell invasion; 2) define the functional relationships among Hyr1 and the cell surface invasins Als3 and Ssa1 in vitro and in vivo; and 3) define additional Pathway I and II genes that function during OPC. The results from this research will provide new insight into the mechanisms by which C. albicans invades oral epithelial cells and down-regulates neutrophil fungicidal mechanisms. Not only will these data provide a deeper understanding of the pathogenesis of OPC, but they also hold promise to identify new potential drug and vaccine targets.