Candida albicans Epithelial Cell Interactions and Oropharyngeal Disease

白色念珠菌上皮细胞相互作用与口咽疾病

• 批准号: 8269086
• 负责人: Scott G Filler
• 金额: $ 34.7万
• 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: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269086
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Antifungal Agents; Azole resistance; Azoles; Binding; Candida albicans; Cell Communication; Cell Surface Proteins; Cell Wall; Cell surface; Characteristics; Chitinase; Complex; Data; Defect; Development; Diabetes Mellitus; Disease; E-Cadherin; Endocytosis; Epithelial Cells; Foundations; Funding; Gene Targeting; Genes; Goals; Grant; HIV; Head and Neck Cancer; Hexose Transporter; Highly Active Antiretroviral Therapy; Host Defense Mechanism; Immune; Immunocompromised Host; Immunosuppression; In Vitro; Incidence; Individual; Invaded; Mediating; Microarray Analysis; Morbidity - disease rate; Mus; Neutropenia; Opportunistic Infections; Oral; Organism; Oropharyngeal; Pathogenesis; Pathogenicity; Patients; Phosphotransferases; Play; Population Heterogeneity; Public Health; Receptor Cell; Receptor Protein-Tyrosine Kinases; Research; Role; Signal Transduction Pathway; Sjogren' s Syndrome; Specific qualifier value; Steroids; Therapeutic; Virulence; Work; base; cell injury; complement 1q receptor; human PHEMX protein; insight; meetings; mouse model; mutant; new therapeutic target; novel strategies; novel therapeutics; oropharyngeal thrush; overexpression; pathogen; patient population; prevent; public health relevance; receptor binding

DESCRIPTION (provided by applicant): Candida albicans is an opportunistic pathogen that causes oropharyngeal disease in a large and diverse population of patients, including those with HIV/AIDS, Sjogren's syndrome, diabetes mellitus, and cancer of the head and neck. Azole antifungal agents are the current mainstay of therapy for oropharyngeal candidiasis. However, because of the emergence of azole resistance, it is critical to develop novel strategies to prevent and treat this disease. Our goal is to identify new C. albicans virulence genes and to determine the mechanisms by which they contribute to pathogenicity. This information holds promise to identify new therapeutic targets for antifungal strategies. C. albicans invades oral epithelial cells by inducing its own endocytosis. In the previous project period, we discovered that C. albicans Als3 is an invasin that binds to E-cadherin on the epithelial cell surface and induces the endocytosis of the organism. Recently, we have determined that there are additional epithelial cell surface proteins that mediate endocytosis. These epithelial cell surface proteins include the globular C1q receptor (gC1qR) and the Met receptor tyrosine kinase. Also, the tetraspanin, CD151 likely organizes E-cadherin, gC1qR, and Met into a functional complex. We have also discovered that the C. albicans kinase, Tpk2 governs the capacity of C. albicans to invade and damage oral epithelial cells in vitro, as well as cause oropharyngeal candidiasis in mice. Further, Tpk2 governs the expression of the C. albicans chitinase, Cht2 and hexose transporter, Hgt12, which play key roles in C. albicans interaction with epithelial cells. In this project, we will 1) determine the functional interactions among E-cadherin, gC1qR, Met, and CD151 in epithelial cell invasion and damage by C. albicans; 2) determine the mechanisms by which C. albicans Cht2 and Hgt12 govern epithelial cell invasion, damage, and virulence; and 3) use overexpression-rescue and null mutant analysis to identify additional target genes of Tpk2 that mediate epithelial cell invasion and damage. PUBLIC HEALTH RELEVANCE: This research is highly relevant to public health because oropharyngeal candidiasis is a frequent cause of morbidity in patients with HIV/AIDS, Sjogren's syndrome, diabetes mellitus, and head and neck cancers. Although azole antifungals are currently the mainstay of therapy for oropharyngeal candidiasis, the emergence of azole resistance makes it necessary to develop new strategies to prevent and treat this disease. Discovering the C. albicans genes and host cell receptors that govern epithelial cell invasion and damage holds promise to provide new insight into the pathogenesis of oropharyngeal candidiasis. Furthermore, this information may be used to develop new therapeutic strategies against this highly prevalent disease.

描述（由申请人提供）：白色念珠菌是一种机会性病原体，可在大量不同的患者群体中引起口咽疾病，包括艾滋病毒/艾滋病、干燥综合征、糖尿病和头颈癌患者。唑类抗真菌药是目前口咽部念珠菌病的主要治疗方法。然而，由于唑类耐药性的出现，开发新的策略来预防和治疗这种疾病至关重要。我们的目标是鉴定新的白色念珠菌毒力基因并确定它们导致致病性的机制。这些信息有望确定抗真菌策略的新治疗靶点。 白色念珠菌通过诱导其自身的内吞作用侵入口腔上皮细胞。在前期项目期间，我们发现白色念珠菌Als3是一种侵袭素，能够与上皮细胞表面的E-钙粘蛋白结合，诱导机体的内吞作用。最近，我们确定还有其他介导内吞作用的上皮细胞表面蛋白。这些上皮细胞表面蛋白包括球状 C1q 受体 (gC1qR) 和 Met 受体酪氨酸激酶。此外，四跨膜蛋白 CD151 可能将 E-钙粘蛋白、gC1qR 和 Met 组织成功能复合物。我们还发现，白色念珠菌激酶 Tpk2 控制着白色念珠菌在体外侵入和损伤口腔上皮细胞的能力，以及引起小鼠口咽部念珠菌病的能力。此外，Tpk2 控制白色念珠菌几丁质酶、Cht2 和己糖转运蛋白 Hgt12 的表达，它们在白色念珠菌与上皮细胞的相互作用中发挥关键作用。在这个项目中，我们将1)确定E-cadherin、gC1qR、Met和CD151在白色念珠菌侵袭和损伤上皮细胞中的功能相互作用； 2)确定白色念珠菌Cht2和Hgt12控制上皮细胞侵袭、损伤和毒力的机制； 3) 使用过表达拯救和无效突变分析来鉴定介导上皮细胞侵袭和损伤的 Tpk2 的其他靶基因。 公共健康相关性：这项研究与公共健康高度相关，因为口咽念珠菌病是艾滋病毒/艾滋病、干燥综合征、糖尿病和头颈癌患者发病的常见原因。虽然唑类抗真菌药物目前是口咽部念珠菌病的主要治疗方法，但唑类耐药性的出现使得有必要开发新的策略来预防和治疗这种疾病。发现控制上皮细胞侵袭和损伤的白色念珠菌基因和宿主细胞受体有望为口咽念珠菌病的发病机制提供新的见解。此外，这些信息可用于开发针对这种高度流行的疾病的新治疗策略。