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 Furthermore, in our unpublished preliminary data we show: 1.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细分，导致严重的微生物 营养不良和慢性免疫激活最终促进疾病进展。而且，一个破坏了一个 在最了解的粘膜环境中，在艾滋病毒引起的免疫抑制过程中，口腔可以 导致念珠菌病，坏死性牙龈炎，牙周炎，毛茸茸的白细胞病，口腔肿瘤增加，也可以 在其他地方有助于并预测盘中疾病并发症。 RORγT+先天淋巴样细胞3型（ILC3） 产生IL-17和IL-22，对于维持胃肠道上皮的完整性至关重要，介导粘膜 共生菌群的抗菌防御和稳定性，但其他人最近显示出大量 ILC3数量和功能的系统性改变 Reeves，Front Immunol，2013年； Li等人，PLOS Path，2014年）。此外，在我们未发表的初步 我们显示的数据：1。SIV感染在口腔中诱导高度炎症和细胞毒性ILC3表型。 2。使用一种新型的ILC3耗尽抗体在口服，结直肠和阴道粘膜中的有效部署 由我们的实验室专门用于恒河猕猴。 3。特定微生物种类的营养不良与 慢性免疫激活；和4。益生菌治疗可在SIV感染期间降低免疫激活 诱导粘膜功能性ILC3数的扩展。在这个创新和变革性的建议中 我们将评估核心假设，即ILC3充当粘膜敏感且可定位的调节剂 口腔中的体内稳态，免疫激活和微生物群通过三个完整的特定目的： 1。实验确定ILC在调节口服微生物组和口服粘膜中的作用 稳态； 2。定义SIV感染的动力学，激活和详细的免疫学影响 口腔中的ILC和微生物组；和3。研究益生菌治疗对口服ILC的影响 在慢性治疗和未处理的SIV感染期间的微生物组。