C. albicans-Epithelial Interactions & Oropharyngeal Disease

白色念珠菌-上皮相互作用

• 批准号: 7006239
• 负责人: Scott G Filler
• 金额: $ 34.12万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006239
• 关键词: Candida albicans; RNA interference; candidiasis; cell surface receptors; drug resistance; fungal genetics; gastrointestinal epithelium; gene expression profiling; genetic manipulation; genetic transcription; host organism interaction; laboratory mouse; mutant; opportunistic infections; oral pharyngeal disorder; receptor binding; small interfering RNA; virulence

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. 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 Dromise to identify new targets for antifungal strategies. During an oropharyngeal infection, C. albicans invades and damages oral epithelial cells. We have found that many C. albicans mutants with decreased virulence in the mouse model of oropharyngeal candidiasis also have reduced ability to invade and damage oral epithelial cells in vitro. Therefore, we hypothesize that the capacity of C. albicans to invade and damage oral epithelial cells is critical for the organism to establish and maintain an oropharyngeal infection. Our objective is to use in vitro studies of the interactions between C. albicans and oral epithelial cells to define mechanisms of host-pathogen interaction. Specifically, we will determine the mechanisms by which C. albicans invades and injures oral epithelial cells through the following aims. (1) We will identify the epithelial cell receptors that C. albicans uses to invade this host cell. (2) We will use our existing information on the transcriptional response of C. albicans to oral epithelial cells to identify C. albicans genes encoding potential virulence factors that are necessary for oral epithelial cell damage. The function of these genes will be investigated by constructing insertion and overexpression mutants. These mutants will be screened for their ability to damage epithelial cells in vitro. (3) Mutants with epithelial cell damage defects will be analyzed further by determining the epithelial cell receptors to which they bind, their ability to invade oral epithelial cells in vitro, and their virulence in the mouse model of oropharyngeal candidiasis. (4) The functional relationships among C. albicans virulence genes will be elucidated by transcriptional profiling and epistasis analysis using both newly created and existing C. albicans mutants.

描述（由申请人提供）：白色念珠菌是一种机会性病原体，在包括HIV/AIDS的大量患者中引起大量多样化的患者。硫杆菌念珠菌病的当前治疗中的主要支柱。但是，由于硫唑耐药性的出现，制定预防和治疗这种疾病的新型策略至关重要。我们的目标是鉴定白色念珠菌的毒力基因，并确定它们对致病性有助的机制。该信息持有dromise，以确定抗真菌策略的新目标。在口咽感染期间，白色念珠菌侵入和损害口腔上皮细胞。我们发现，在口咽念珠菌病小鼠模型中，许多具有毒力降低的白色念珠菌突变体也具有降低的体外侵入和损害口服上皮细胞的能力。因此，我们假设白色念珠菌入侵和损害口腔上皮细胞的能力对于生物体建立和维持口咽感染至关重要。我们的目标是在体外研究白色念珠菌和口腔上皮细胞之间的相互作用来定义宿主 - 病原体相互作用的机制。具体而言，我们将确定白色念珠菌通过以下目的侵入和损害口腔上皮细胞的机制。 （1）我们将确定白色念珠菌用来侵入该宿主细胞的上皮细胞受体。 （2）我们将使用有关白色念珠菌对口腔上皮细胞的转录反应的现有信息来识别编码对口腔上皮细胞损伤所必需的潜在毒力因子的白色念珠菌基因。这些基因的功能将通过构建插入和过表达突变体来研究。这些突变体将因其体外损害上皮细胞的能力而进行筛选。 （3）将通过确定其结合的上皮细胞受体，其在体外侵袭口腔上皮细胞的能力以及在小鼠口咽念珠菌病模型中的毒力，进一步分析具有上皮细胞损伤缺陷的突变体。 （4）使用新创建的白色念珠菌突变体和现有的白色念珠菌突变体，将通过转录分析和上毒分析来阐明白色念珠菌毒力基因之间的功能关系。