Defense of oral epithelial cells from candida by hBDs

hBD 保护口腔上皮细胞免受念珠菌侵害

• 批准号: 7095126
• 负责人: AARON WEINBERG
• 金额: $ 26.4万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095126
• 关键词: Candida albicans; Fusobacterium nucleatum; HIV infections; bacteria infection mechanism; biological signal transduction; cytokine; defensins; disease /disorder model; enzyme linked immunosorbent assay; gene expression; genetically modified animals; human subject; human tissue; laboratory mouse; messenger RNA; microarray technology; oral mucosa; toll like receptor

Oral candidal infections are re-emerging owing to the prevalence of AIDS in the under-developed world, where highly active antiretroviral therapy (HAART) is not available, in cases where resistance to HAART develops and in misuse of antibiotics. Recent findings point to mucosal epithelial cells as the sources of antibacterial and antifungal agents, belonging to a family of small, cationic peptides called human beta-defensins (hBDs). We recently discovered a novel strategy by which F. nucleatum, a ubiquitous organism of the oral cavity, protects human oral epithelial cells (HOECs) by inducing hBDs. Since they can kill the fungal pathogen Candida albicans, act as chemoattractants towards dendritic cells (DCs), monocytes and T cells and can induce maturation of DCs and monocytes, one can surmise the importance of these agents in preventing fungal infection at mucosal surfaces, and/or controlling C. albicans replication until acquired immune cells are recruited to the local site. This proposal intends to test hypotheses emanating from the postulate that oral epithelial cells can be stimulated to produce beta-defensins that protect the host from fungal challenges at the oral mucosal barrier. Since the role of hBDs in protecting the oral mucosal epithelium from fungal biofilm growth, the mechanisms by which they are regulated when cells are confronted by a beneficial versus opportunistic organism, the presence of other HOEC derived antimicrobial peptides, or whether hBD expression is altered in HOECs as a result of HIV, have never been systematically studied, we offer the following objectives: (1) to determine the importance of hBDs against C. albicans following F. nucleatum activation in human oral epithelial cells (HOECs) from HIV- and HIV+ individuals and (2) to define HOEC responses to C. albicans challenge as regards cytokine expression and utilization of toll-like receptors and intracellular signaling pathways. . In light of the frequent adjunctive use of antibiotics and antimycotics in treating oral diseases, with the threat of microbial resistance, investigations into novel eukaryotic peptides, such as beta-defensins, are highly significant and offer the potential for future clinical promise. This novel research direction is viewed as extremely significant in leading to future studies that have potential application to oral disorders, therapuetic use, and technology development.

由于艾滋病在不发达国家的流行，口腔念珠菌感染重新出现，而在这些国家，如果对HAART产生耐药性并且滥用抗生素，则无法获得高效的抗逆转录病毒疗法（HAART）。最近的研究结果表明，粘膜上皮细胞是抗菌剂和抗真菌剂的来源，属于称为人类β-防御素（hBD）的小型阳离子肽家族。我们最近发现了一种新策略，口腔中普遍存在的具核梭杆菌通过诱导 hBD 来保护人类口腔上皮细胞 (HOEC)。由于它们可以杀死真菌病原体白色念珠菌，作为树突状细胞 (DC)、单核细胞和 T 细胞的化学引诱剂，并且可以诱导 DC 和单核细胞的成熟，因此人们可以推测这些药剂在预防粘膜表面真菌感染方面的重要性，以及/或控制白色念珠菌复制直至 获得性免疫细胞被招募到局部部位。该提案旨在测试源自假设的假设，即口腔上皮细胞可以被刺激产生β-防御素，保护宿主免受口腔粘膜屏障的真菌挑战。 由于 hBD 在保护口腔粘膜上皮免受真菌生物膜生长方面的作用， 当细胞面对有益生物体与机会生物体时，它们的调节机制、其他 HOEC 衍生的抗菌肽的存在，或者 HOEC 中的 hBD 表达是否因 HIV 而改变，尚未得到系统研究，我们提供以下内容目标：(1) 确定 HIV-和 HIV+ 个体的人口腔上皮细胞 (HOEC) 中具核梭菌激活后 hBD 对白色念珠菌的重要性，以及 (2) 定义 HOEC 对白色念珠菌在细胞因子表达和 Toll 样受体的利用以及细胞内信号通路方面面临挑战。 。 鉴于在治疗口腔疾病时频繁辅助使用抗生素和抗真菌剂，以及微生物耐药性的威胁，对新型真核肽（例如β-防御素）的研究具有非常重要的意义，并为未来的临床前景提供了潜力。这一新颖的研究方向被认为对于未来研究具有极其重要的意义，这些研究可能应用于口腔疾病、治疗用途和技术开发。