C. albicans invasion and proliferation during oral infection

口腔感染期间白色念珠菌的侵袭和增殖

• 批准号: 9894647
• 负责人: Scott G Filler
• 金额: $ 58.44万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894647
• 关键词: AIDS diagnosis; AIDS/HIV problem; Abbreviations; Acquired Immunodeficiency Syndrome; Adherence; Antifungal Agents; Azole resistance; Azoles; Binding; Biological Assay; Biopsy Specimen; Candida; Candida albicans; Cell Surface Proteins; Cell surface; Cells; Chronic Granulomatous Disease; Data; Development; Diabetes Mellitus; Disease; E-Cadherin; ERBB2 gene; Endocytosis; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Epithelium; Esophagus; Foundations; Gene Expression Profiling; Genes; HGF gene; Immunocompromised Host; Immunotherapy; In Vitro; Individual; Industrial fungicide; Infection; InlB protein; Invaded; Leukocytes; Membrane Proteins; Modeling; Morbidity - disease rate; Mus; Mutation; Neutropenia; Newly Diagnosed; Organism; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Periodic acid Schiff stain method; Phagocytes; Pharmaceutical Preparations; Pharmacology; Population Heterogeneity; Public Health; Reactive Oxygen Species; Receptor Protein-Tyrosine Kinases; Recombinant Proteins; Regulation; Research; Role; Sampling; Steroids; Testing; Vaccines; Virulence; base; diphenyliodonium; extracellular; gene discovery; gene function; genome database; in vitro Assay; in vivo; inhibitor/antagonist; insight; member; microbial; mouse model; mutant; neutrophil; novel diagnostics; novel strategies; novel therapeutic intervention; oral cavity epithelium; oral infection; oropharyngeal thrush; prevent; prospective; receptor; transcription factor; transcriptome sequencing

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.

抽象的 口咽念珠菌病 (OPC) 在大量不同的人群中引起显着的发病率，尤其是 由于艾滋病、中性粒细胞减少症、糖尿病或使用类固醇而导致免疫功能低下的患者。在 事实上，据估计每年发生近 1000 万例与 HIV/艾滋病相关的 OPC 病例，其中近五分之一 这些人中有食管受累。唑类抗真菌药物是目前的主要治疗方法 对于OPC。然而，由于唑类抗药性的出现，开发新的策略至关重要 预防和治疗 OPC。 我们的研究集中在这样的假设上：白色念珠菌基因促进粘附和入侵 上皮细胞的数量对于有机体引起 OPC 至关重要。这个假说是基于这样一个事实：入侵 OPC 期间会发生浅表上皮细胞的变化，OPC 患者的活检标本可揭示微生物 口腔上皮细胞内。粘附/侵袭功能是由细胞表面蛋白相互作用来实现的 宿主细胞上的同源受体。这些相互作用使生物体能够侵入口腔上皮细胞并避免 被吞噬细胞杀死。我们的数据表明，有两种粘附/侵袭途径在发挥作用 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。我们的研究中新描述了途径 II 初步结果。通路 II 包括白色念珠菌表面蛋白 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。我们的总体前提是途径 I 和 途径 II 通过 E-钙粘蛋白促进口腔上皮细胞对白色念珠菌的内吞作用。途径二也 当白色念珠菌与中性粒细胞相互作用时发挥作用，抑制中性粒细胞的杀伤。 拟议研究的目的是测试通路 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和上皮细胞侵袭的相互作用； 2）定义泛函 Hyr1与细胞表面侵袭素Als3和Ssa1在体外和体内的关系； 3) 定义额外的 在 OPC 期间发挥作用的途径 I 和 II 基因。这项研究的结果将为我们提供新的见解 白色念珠菌侵入口腔上皮细胞并下调中性粒细胞杀菌作用的机制 机制。这些数据不仅可以让人们更深入地了解 OPC 的发病机制，而且 还有望确定新的潜在药物和疫苗靶点。