The oral mucosal proteome: perturbation in HIV infection and Candida co infection

口腔粘膜蛋白质组：HIV 感染和念珠菌合并感染的扰动

• 批准号: 7114687
• 负责人: STEPHEN J CHALLACOMBE
• 金额: $ 27万
• 依托单位: KING'S COLLEGE LONDON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-17 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7114687
• 关键词: Candida; HIV infections; clinical research; epithelium; human; infection; model; oral mucosa; proteins; proteomics

DESCRIPTION (provided by applicant): This multidisciplinary application supports a strategy of combining patient-oriented research with the science based investigation of disease causation. The overall aim is to understand the mechanisms that apparently protect the oral epithelium from HIV infection. The long-term objective is to understand the basis of copathogenicity in the immunocompromised host leading to the delivery of more effective therapies. We hypothesize that HIV directly affects the oral epithelial proteome, leading to alterations that promote colonization and infection of the co-pathogen Candida. The specific aims are: 1) To fully characterize the constituents of the oral epithelium that protects the oral mucosa from HIV and Candida infection. Using oral and vaginal epithelial models, and human and macaque samples, the canonical receptors for both HIV and Candida will be investigated by flow cytometry. The epithelial proteome in the presence or absence of HIV and Candida will be then be fully characterized in order to identify protective or susceptibility factors to HIV and Candida infection in these mucosae. Saliva will be applied to the models to investigate the contribution of innate secretory factors present in oral fluids that may inhibit HIV or Candida infection Transcript profiling, quantitative RT-PCR, and Luminex protein assays will be performed to support the proteomic data. 2) To characterize the innate TLR-associated proteomic response elicited by human epithelium during HIV and Candida infection. The HIV- and C. a/b/cans-induced epithelial cytokine, chemokine, TLR1-10 and signaling pathway expression profiles will first be characterized in oral and vaginal epithelial models using proteomics. The PMN-dependent TLR-mediated protection mechanism against oral C. albicans infection will then be fully characterized using transcript profiling, real-time RT-PCR, confocal and immunoelectron microscopy, and siRNAi. Relevance: HIV/AIDS is most commonly transmitted through mucosal membranes. In some circumstances, the oral tissues are exposed to HIV but rarely become infected. Understanding the mechanism by which the oral cavity is apparently protected from infection could lead to the development of therapies to protect other mucosal tissues such as the vagina from infection and transmission of the virus. This could also lead to therapies for the treatment of the co-infections associated with HIV such as oral Thrush.

描述（由申请人提供）：该多学科应用支持将以患者为导向的研究与基于科学的疾病病因调查相结合的策略。总体目标是了解保护口腔上皮免受HIV感染的机制。长期目标是了解免疫功能低下宿主中共致病性的基础，从而提供更有效的治疗。我们假设HIV直接影响口腔上皮蛋白质组，导致改变，促进共同病原体念珠菌的定植和感染。具体目标是：1）充分表征保护口腔粘膜免受HIV和念珠菌感染的口腔上皮成分。使用口腔和阴道上皮模型以及人和猕猴样本，将通过流式细胞术研究HIV和念珠菌的典型受体。然后将充分表征存在或不存在HIV和念珠菌的上皮蛋白质组，以鉴定这些粘膜中对HIV和念珠菌感染的保护性或易感性因子。将唾液应用于模型，以研究可能抑制HIV或念珠菌感染的口腔液中存在的先天分泌因子的贡献。将进行转录谱分析、定量RT-PCR和Luminex蛋白测定，以支持蛋白质组学数据。2)描述HIV和念珠菌感染过程中人类上皮细胞引发的先天性TLR相关蛋白质组学反应。HIV和C. a/B/cans诱导的上皮细胞因子、趋化因子、TLR 1 -10和信号传导途径表达谱将首先在口腔和阴道上皮模型中使用蛋白质组学进行表征。PMN依赖的TLR介导的抗口腔念珠菌的保护机制。然后使用转录谱、实时RT-PCR、共聚焦和免疫电子显微镜以及siRNAi来充分表征白色念珠菌感染。相关性：艾滋病毒/艾滋病最常通过粘膜传播。在某些情况下，口腔组织暴露于艾滋病毒，但很少被感染。了解口腔明显免受感染的机制可能会导致开发保护其他粘膜组织（如阴道）免受病毒感染和传播的治疗方法。这也可能导致治疗与艾滋病毒相关的合并感染的疗法，如口服鹅口疮。