Microbial and innate immune mechanisms of oral inflammation during SIV infection

SIV感染期间口腔炎症的微生物和先天免疫机制

• 批准号: 10408915
• 负责人: Roger Keith Reeves
• 金额: $ 20.93万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-03 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408915
• 关键词: Microbial; innate; immune; mechanisms; oral

HIV/SIV infections lead to a breakdown of the integrity of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression can result in candidiasis, necrotizing gingivitis, periodontitis, hairy leukoplakia, increased oral tumors, and can also contribute to and predict distal disease complications elsewhere. RORγt+ innate lymphoid cells type 3 (ILC3) produce IL-17 and IL-22 and are vital for maintaining the integrity of the GI epithelium, mediating mucosal antimicrobial defense and stability of commensal microflora, but others and we have recently shown massive, systemic alterations in ILC3 numbers and functions in the oral, reproductive and gastrointestinal mucosae (Li and Reeves, Front Immunol, 2013; Li et al., PLoS Path, 2014). Furthermore, in our unpublished preliminary data we show: 1. SIV infection induces a highly inflammatory and cytotoxic ILC3 phenotype in the oral cavity; 2. Efficient depletion in oral, colorectal, and vaginal mucosae using a novel ILC3-depleting antibody developed by our laboratory specifically for rhesus macaques. 3. Dysbiosis of specific microbial species is associated with chronic immune activation; and 4. Probiotic therapy reduces immune activation during SIV infection and induces expansion of functional ILC3 numbers in the mucosae. In this innovative and transformative proposal we will evaluate the core hypothesis that ILC3 act as a sensitive and targetable modulator for mucosal homeostasis, immune activation, and microflora in the oral cavity through three complementary specific aims: 1. Experimentally determine the role of ILCs in modulating the oral microbiome and oral mucosae homeostasis; 2. Define the kinetics, activation, and detailed immunologic effects of SIV infection on ILCs and microbiome in the oral cavity; and 3. Investigate the effects of probiotic therapy on oral ILCs and microbiome during chronic treated and untreated SIV infection.

HIV/SIV感染导致上皮粘膜完整性的破坏，导致严重的微生物 生物失调和慢性免疫激活，最终推动疾病进展。此外，其中一个的中断 在研究最少的粘膜环境中，口腔在HIV诱导的免疫抑制过程中可以 导致念珠菌病、坏死性牙周炎、牙周炎、毛发白斑、口腔肿瘤增多，还可 有助于并预测其他地方的远端疾病并发症。RoRγt+3型先天淋巴细胞(ILC3) 产生IL-17和IL-22，对维持胃肠道上皮的完整性至关重要，介导粘膜 抗菌防御和共生微生物群的稳定性，但其他人和我们最近已经显示出大量的， 口腔、生殖和胃肠粘膜中ILC3数量和功能的系统性变化(LI 和里夫斯，前线免疫，2013；Li等人，PLoS Path，2014)。此外，在我们未发表的初步报告中 研究结果表明：1.SIV感染可诱导口腔中高度炎症和细胞毒的ILC3表型； 2.使用开发的新的ILC3耗竭抗体在口腔、结直肠和阴道粘膜中有效地清除 由我们的实验室专门为恒河猴设计。3.特定微生物物种的生态失调与 慢性免疫激活；以及4.益生菌治疗降低SIV感染和 诱导黏膜中功能性ILC3数量的扩张。在这一创新和变革性的提案中 我们将评估ILC3作为一种敏感的和靶向的粘膜调节剂的核心假设 口腔内的动态平衡、免疫激活和微生物区系通过三个互补的特定目标： 1.实验确定ILCs对口腔微生物群和口腔粘膜的调节作用 定义SIV感染的动力学、激活和详细的免疫学影响 口腔中的ILCs和微生物组；3.研究益生菌治疗对口腔ILCs的影响 在慢性治疗和未经治疗的SIV感染期间的微生物群。