Oral Epithelial Cell Cytokines Candida & PMN Activation

口腔上皮细胞细胞因子念珠菌

• 批准号: 7082815
• 负责人: Anna I Dongari-Bagtzoglou
• 金额: $ 31.86万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-29 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082815
• 关键词: Candida albicans; candidiasis; cell migration; cellular immunity; clinical research; colony stimulating factor; confocal scanning microscopy; cytokine; flow cytometry; fluorescence microscopy; gingiva; host organism interaction; human subject; interleukin 1; leukocyte activation /transformation; mixed tissue /cell culture; mucosal immunity; neutrophil; oral mucosa; pathologic process; phagocytosis; statistics /biometry

DESCRIPTION: In oropharyngeal candidiasis a breakdown of the mucosal innate defenses and decreased polymorphonuclear cell number or function result in the transition from oral commensalism to mucosal infection. The overall goal of this competitive renewal is to continue studies on the oral mucosal inflammatory responses to Candida albicans and the regulatory role of these responses on the function of innate immune cells and Candida clearance. Data from our laboratory indicate the existence of a cytokine communication network between oral epithelial cells, fibroblasts and innate immune cells with potentially important consequences in the inflammatory response to this pathogen and the clearance of this infection in vivo. So far we have studied these interactions between multiple cell types using a single cell system approach. To overcome some of the imitations associated with single cell culture systems we propose to use an artificial tissue culture system, incorporating saliva, oral epithelial cells and fibroblasts, in an attempt to mimic the oral masticatory mucosa and submucosa. We will also incorporate an immunological component in a modification of this system by adding peripheral blood neutrophils and examining their migratory and candidacidal activities. The novelty and additional benefit from this approach is that the mucosal-submucosal cell dialogue can be monitored simultaneously during infection, taking into account complex cell-cell contact interactions and interactions that are carried out via secreted cytokines. Using these novel tissue culture approaches we propose to study: a) the role of proinflammatory cytokines in neutrophil transepithelial migration and Candida clearance; b) the role of germination-dependent gene products in C. albicans virulence; and c) the virulence of C. glabrata in a mono-infection and co-infection models. Identification of candidate cytokine effectors which are involved in the innate immune cell activation and C. albicans genes which promote invasive infection will provide novel therapeutic targets within the C. albicans-oral mucosal response framework.

描述：在口咽念珠菌病中，粘膜固有防御系统的破坏和多形核细胞数量或功能的减少导致从口腔共生向粘膜感染的转变。本次竞争性更新的总体目标是继续研究口腔黏膜对白色念珠菌的炎症反应，以及这些反应对天然免疫细胞功能和念珠菌清除的调节作用。我们实验室的数据表明，口腔上皮细胞、成纤维细胞和先天免疫细胞之间存在细胞因子通讯网络，在体内对这种病原体的炎症反应和这种感染的清除具有潜在的重要后果。到目前为止，我们已经使用单细胞系统方法研究了多种细胞类型之间的这些相互作用。为了克服一些与单细胞培养系统相关的模仿，我们建议使用人工组织培养系统，结合唾液、口腔上皮细胞和成纤维细胞，试图模拟口腔咀嚼粘膜和粘膜下层。我们还将在这个系统的改进中加入免疫学成分，增加外周血中性粒细胞，并检查它们的迁移和杀灭念珠菌的活性。这种方法的新颖性和额外的好处是，考虑到复杂的细胞-细胞接触相互作用和通过分泌的细胞因子进行的相互作用，可以在感染期间同时监测粘膜-粘膜下细胞对话。利用这些新的组织培养方法，我们建议研究：a)促炎症细胞因子在中性粒细胞跨上皮迁移和念珠菌清除中的作用；b)发芽依赖基因产物在白念珠菌毒力中的作用；以及c)光滑念珠菌在单一感染和混合感染模型中的毒力。识别参与天然免疫细胞激活的候选细胞因子效应因子和促进侵袭性感染的白念珠菌基因，将在白念珠菌口腔黏膜反应框架内提供新的治疗靶点。