Molecular pathology of oral immune dysregulation in HIV/SIV infection

HIV/SIV 感染口腔免疫失调的分子病理学

• 批准号: 10133355
• 负责人: Mahesh Mohan
• 金额: $ 8.2万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2020-09-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133355
• 关键词: Molecular; pathology; oral; immune; dysregulation

ABSTRACT Although, innate and adaptive immune functions are maintained in the oral mucosa during acute HIV/SIV infection, these responses become markedly impaired during chronic HIV infection and are not fully restored by combination anti-retroviral therapy (cART). Persistent oral mucosal inflammation/immune activation characterized by dysregulated proinflammatory cytokine production and oral dysbiosis are cardinal features of chronic HIV/SIV infection. Even though our understanding of oral mucosal dysfunction in HIV/SIV infection has improved, the underlying molecular mechanisms remain unknown and unexplored. Apart from cytokines and transcription factors, recent studies show microRNA (miRNA)-mediated gene regulation to be critical for immune cell differentiation, maturation, activation and inflammatory responses. Extensive studies in other chronic inflammatory diseases of the oral cavity (Periodontitis, Oral lichen planus. etc.) have revealed a causative role for miRNAs in disease pathogenesis resulting in their identification as promising therapeutic targets. However, the role of miRNAs in HIV induced oral mucosal dysfunction is lacking. This application builds on preliminary studies, which identified significant dysregulation of miRNAs linked to T and B-cell activation and epithelial barrier disruption in tonsils and buccal mucosa (BUCM) from chronically SIV-infected rhesus macaques. Studies of the same group using delta-9-tetrahydrocannabinol (⁹-THC) administration to chronic SIV-infected RMs significantly suppressed gastrointestinal proinflammatory gene/miRNA expression and inhibited T and B-cell activation and proliferation in vitro, suggesting their immense therapeutic potential for attenuating/reversing local (oral cavity) and systemic immune activation and slowing disease progression in the setting of suppressive cART. Based on our strong preliminary data demonstrating that miRNA expression is dysregulated in BUCM and tonsils in chronic HIV/SIV infection, we hypothesize that this leads to oral mucosal dysfunction, which contributes to immune activation and HIV disease progression. Further, we hypothesize that chronic ⁹-THC treatment may reduce inflammation, restore oral immune function, and slow HIV/SIV disease progression by modulating miRNA expression. A major goal of this application is to identify miRNA mechanisms associated with oral mucosal dysfunction and cannabinoid mediated suppression of immune activation. The project has three specific aims: 1) Test the hypothesis that miRNA (miR-142-3p,-142- 5p,-186,-7,-101-3p,-29b,-141) mediated downregulation of occludin (OCLN), claudin-1 (CLDN1) and zona occludens (ZO1) leads to oral epithelial barrier breakdown and increased epithelial permeability. 2) Identify miRNA mechanisms of cannabinoid-induced suppression of immune activation in BUCM and tonsils during the course of SIV infection. 3) Determine the effect of combination anti-retroviral treatment (cART) in conjunction with chronic ⁹-THC administration on the oral microflora, inflammation/immune activation, viral replication, miRNA expression and epithelial tight junction proteins in the oral cavity. The proposed research is novel and applies state of the art immunological and molecular approaches to address a significant gap in our understanding of the transcriptional and post-transcriptional mechanisms underlying oral mucosal dysfunction in the setting of suppressive cART. Additionally and more importantly, the results will deepen our understanding of the mechanisms underlying the anti-inflammatory effects of cannabinoids and have important therapeutic implications for targeted immune modulation in not only HIV but also other chronic inflammatory diseases of the oral cavity. Thus, the overall significance and impact is high.

摘要 虽然，在急性HIV/SIV期间，口腔粘膜中的先天和获得性免疫功能是保持的 在慢性HIV感染期间，这些反应会明显受损，并不能完全恢复到 联合抗逆转录病毒疗法(CART)。持续性口腔黏膜炎症/免疫激活 以促炎细胞因子产生失调和口腔微生物失调为主要特征 慢性艾滋病毒/SIV感染。即使我们对HIV/SIV感染中口腔粘膜功能障碍的理解 经过改进，潜在的分子机制仍然未知和未被探索。除了细胞因子和 转录因子，最近的研究表明，microRNA(MiRNA)介导的基因调控对 免疫细胞分化、成熟、激活和炎症反应。对其他领域的广泛研究 口腔慢性炎症性疾病(牙周炎、口腔扁平苔藓。等)揭示了一种 MiRNAs在疾病发病机制中的致病作用使其被认为是有希望的治疗方法 目标。然而，miRNAs在HIV诱导的口腔粘膜功能障碍中的作用尚不清楚。此应用程序 建立在初步研究的基础上，这些研究发现与T和B细胞相关的miRNAs存在显著的失调 慢性SIV感染患者扁桃体和颊粘膜上皮屏障的激活和破坏 恒河猴。同一组人应用⁹-THc给药的研究 慢性SIV感染的RMS显著抑制胃肠道促炎基因/miRNA的表达 并在体外抑制T和B细胞的激活和增殖，表明它们具有巨大的治疗潜力 减轻/逆转局部(口腔)和全身免疫激活，延缓疾病进展 压制小车的设置。基于我们强有力的初步数据表明miRNA的表达 在慢性HIV/SIV感染中，BUCM和扁桃体的调节失调，我们假设这会导致口腔 粘膜功能障碍，这有助于免疫激活和艾滋病毒疾病的进展。此外，我们 假设慢性⁹-Thc治疗可以减少炎症，恢复口腔免疫功能，并减缓 通过调节miRNA的表达使HIV/SIV疾病进展。此应用程序的一个主要目标是识别 与口腔粘膜功能障碍和大麻素介导的抑制相关的miRNA机制 免疫激活。该项目有三个具体目标：1)检验miRNA(miR-142-3p，-142- 5p，-186，-7，-101-3p，-29b，-141)介导的阻滞素(OCLN)、Claudin-1(CLDN1)和小带的下调 闭塞剂(ZO1)导致口腔上皮屏障破坏和上皮通透性增加。2)识别 大麻素抑制BUCM和扁桃体免疫激活的miRNA机制 SIV感染病程。3)确定联合抗逆转录病毒治疗(CART)的效果 慢性⁹-Thc给药对口腔微生物区系、炎症/免疫激活、病毒复制、 口腔黏膜中miRNA的表达与上皮紧密连接蛋白的关系建议的研究是新颖的，而且 应用最先进的免疫学和分子方法来解决我们在 了解口腔粘膜功能障碍的转录和转录后机制 在压制车的背景下。此外，更重要的是，选举结果将加深我们的 了解大麻素抗炎作用的潜在机制并具有重要意义 靶向免疫调节不仅对HIV而且对其他慢性炎症性疾病的治疗意义 口腔疾病。因此，总体意义和影响是很高的。