Epithelial Innate Immune Response to Oral Bacteria

上皮细胞对口腔细菌的先天免疫反应

• 批准号: 7091386
• 负责人: BEVERLY A DALE-CRUNK
• 金额: $ 35.06万
• 依托单位: UNIVERSITY OF WASHINGTON
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091386
• 关键词: Bacteroides gingivalis; Streptococcus; antigen presentation; bacterial cytopathogenic effect; bactericidal immunity; biological signal transduction; clinical research; defensins; endopeptidases; epithelium; gene induction /repression; gingiva; host organism interaction; human tissue; immune response; immunocytochemistry; inflammation; oral bacteria; oral mucosa; periodontium disorder; polymerase chain reaction; receptor expression; tissue /cell culture; toll like receptor; western blottings

DESCRIPTION: This application will analyze the molecular mechanisms utilized by host gingival epithelial cells (GECs) in response to commensal and pathogenic oral bacteria, and the cellular receptors and signaling pathways associated with innate immunity in the periodontium. GECs respond to bacteria in an interactive manner secreting chemokines and cytokines to alert various cell types and attract neutrophils. They also produce natural antimicrobial peptides of the beta-defensin family. The defensin antimicrobial peptides are part of the innate immune system, a complex set of responses that keeps microbial invaders in check and maintains the microbial ecology of the healthy periodontal pocket. Human beta-defensin-2 (hBD-2) expression is upregulated in GECs in response to both commensal and pathogenic bacteria. In addition, this peptide is widely expressed in normal oral mucosa, in contrast to normal epidermis, suggesting that the innate immune responses of normal oral epithelia are at a heightened state of readiness. This application will test the hypotheses that commensal and pathogenic oral bacteria stimulate different networks of genes in gingival epithelial cells (GECs), that commensals prime the state of innate immunity of GECs for increased responsiveness to the environment and to subsequent exposure to pathogens, and that p-defensins are a major influence in this heightened innate immune response. These hypotheses build on evidence that commensal and pathogenic bacteria utilize different signaling pathways for regulation of hBD-2 gene expression and that hBD-2 itself influences innate immune responses and acts as a positive autocrine regulator. Finally, new evidence suggests involvement of the proteinase-activated receptor (PAR) family in innate immune and inflammatory responses. These receptors signal the presence of danger in the environment and contribute to inflammation. A final Aim will examine the function of these receptors to signal in response to Porphyromonas gingivalis, a major periodontopathogen that has proteinases as part of its set of virulence factors. These questions and hypotheses will be examined with the goal to better understand the global responses of GECs to commensal vs. pathogenic bacteria emphasizing gene expression programs and receptors that are critical for innate immune responses. This work will lay the groundwork for identifying new therapeutic targets to prevent and treat periodontal diseases.

描述：该应用将分析宿主牙龈上皮细胞（GEC）对共生和致病性口服细菌的响应，以及与牙周牙周与先天免疫相关的细胞受体和信号传导途径。 GEC以交互方式对细菌反应，分泌趋化因子和细胞因子，以提醒各种细胞类型并吸引中性粒细胞。它们还产生β-防御素家族的天然抗菌肽。防御素抗微生物肽是先天免疫系统的一部分，这是一组复杂的反应，可使微生物入侵者受到检查并保持健康牙周口袋的微生物生态学。人β-防御素-2（HBD-2）表达在GEC中响应于共生和致病性细菌。另外，与正常表皮相比，该肽在正常口服粘膜中广泛表达，这表明正常口服上皮的先天免疫反应处于准备状态的增强状态。该应用将检验称为和致病性的口服细菌在牙龈上皮细胞（GEC）中刺激不同基因网络（GEC）的假设，该基因构成了GEC的先天免疫力，以增加对环境的响应，并随后暴露于病原体，并且P-defensins对这种P-defensins的影响很大，并且对这种P-defensins的影响很高，这是一种高度影响的无性响应。这些假设基于证据表明，共生和致病细菌利用不同的信号通路来调节HBD-2基因表达，并且HBD-2本身会影响先天免疫反应并充当阳性自分泌剂。最后，新的证据表明，蛋白酶激活的受体（PAR）家族参与先天免疫和炎症反应。这些受体标志着环境中存在危险，并导致炎症。最终目标将检查这些受体的功能，以响应牙龈卟啉单胞菌（牙龈卟啉单胞菌），这是一种主要的牙周病原，其蛋白酶是其毒力因子集的一部分。这些问题和假设将以目标进行研究，以更好地了解GEC对共生细菌的全球反应，强调基因表达程序和受体对先天免疫反应至关重要的受体。这项工作将为确定预防和治疗牙周疾病的新治疗靶点奠定基础。