Candida albicans Epithelial Cell Interactions and Oropharyngeal Disease

描述（由申请人提供）：白色念珠菌是一种机会性病原体，可导致大量不同人群的口咽疾病，包括艾滋病毒/艾滋病、干燥综合征、糖尿病和头颈部癌症患者。唑类抗真菌药物是目前治疗口咽念珠菌病的主要药物。然而，由于唑耐药性的出现，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，并确定它们促进致病性的机制。这一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自身内吞作用侵入口腔上皮细胞。在之前的项目期间，我们发现C. Als3是一种与上皮细胞表面的E-cadherin结合并诱导生物体内吞的入侵蛋白。最近，我们已经确定有额外的上皮细胞表面蛋白介导内吞作用。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，四跨蛋白、CD151可能将e -钙粘蛋白、gC1qR和Met组织成一个功能复合物。我们还发现白色念珠菌激酶Tpk2在体外控制白色念珠菌入侵和损伤口腔上皮细胞的能力，并在小鼠中引起口咽念珠菌病。此外，Tpk2调控白色念珠菌几次质酶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起关键作用。在本项目中，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调控上皮细胞侵袭、损伤和毒力的机制；3)利用过表达拯救和零突变分析鉴定Tpk2介导上皮细胞侵袭和损伤的其他靶基因。

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.