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.

抽象的 虽然在急性HIV/SIV期间，在口腔粘膜中维持先天和适应性免疫功能 感染，这些反应在慢性艾滋病毒感染期间显着受损，并且没有完全恢复 组合抗返回病毒疗法（CART）。持续的口服粘膜注射/免疫激活 促炎细胞因子产生和口服失调的特征是 慢性艾滋病毒/SIV感染。即使我们对艾滋病毒/SIV感染中口服粘膜功能障碍的理解具有 改进的，潜在的分子机制仍然未知且出乎意料。除了细胞因子和 转录因子，最近的研究表明，microRNA（miRNA）介导的基因调节对于对 免疫细胞分化，成熟，激活和炎症反应。在其他方面进行的广泛研究 口腔的慢性炎症性疾病（牙周炎，口腔地衣等等）已显示出一种 miRNA在疾病发病机理中的病因作用，导致其鉴定为有希望的治疗 目标。但是，缺乏miRNA在HIV诱导的口服粘膜功能障碍中的作用。此应用程序 建立在初步研究的基础上，该研究确定了与T和B细胞相关的miRNA的明显失调 扁桃体和颊粘膜（BUCM）的激活和上皮屏障破坏受到长期SIV感染的 恒河猕猴。使用delta-9-四氢大麻醇（⁹-THC）给药的同一组的研究 慢性SIV感染的RM显着抑制胃肠道促炎基因/miRNA表达 并在体外抑制T和B细胞的激活和增殖，表明它们的巨大治疗潜力 用于衰减/逆转局部（口腔）和全身免疫激活，并减缓疾病进展 抑制车的设置。基于我们强大的初步数据，表明miRNA表达 在慢性HIV/SIV感染中的BUCM和扁桃体中失调，我们假设这导致口服 粘膜功能障碍，有助于免疫激活和HIV疾病进展。此外，我们 假设慢性⁹-THC治疗可以减少炎症，恢复口服免疫功能，并缓慢 HIV/SIV疾病进展通过调节miRNA表达。该应用程序的主要目标是确定 与口服粘膜功能障碍和大麻素介导的抑制有关的miRNA机制 免疫激活。该项目具有三个特定的目的：1）测试miRNA（miR-142-3p，-142-）的假设 5P，-186，-7，-101-3P，-29B，-141）介导occludin（OCLN），Claudin-1（Cldn1）和Zona的下调下调 封闭剂（ZO1）导致口腔上皮屏障崩溃和上皮渗透性增加。 2）识别 大麻素诱导的miRNA机制在BUCM和扁桃体中抑制免疫激活 SIV感染过程。 3）确定抗逆转录病毒治疗（CAR）在结合中的影响 慢性⁹-THC在口腔微生物上给药，注射/免疫激活，病毒复制， 口腔中的miRNA表达和上皮紧密连接蛋白。拟议的研究是新颖的， 应用最先进的免疫学和分子方法来解决我们的显着差距 了解口服粘膜功能障碍的基础转录和转录后机制 在抑制车的情况下。另外，更重要的是，结果将加深我们 了解大麻素抗炎作用的基础机制，并具有重要的 对靶向免疫调节的治疗意义不仅在HIV中，而且对其他慢性炎症 口腔疾病。这，总体意义和影响很高。