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: 9316584
• 负责人: Roger Keith Reeves
• 金额: $ 67.54万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316584
• 关键词: Abate; Acute; Antibodies; Antifungal Agents; Antiviral Agents; Biology; CD4 Positive T Lymphocytes; Candidiasis; Cell physiology; Chronic; Colorectal; Data; Development; Disease; Disease Progression; Distal; Environment; Epithelial; Gastrointestinal tract structure; Gingivitis; Growth Factor; HIV; Hairy Leukoplakia; Helper-Inducer T-Lymphocyte; Homeostasis; Human Herpesvirus 4; Human Herpesvirus 8; Immune; Immune Tolerance; Immunity; Immunologic Markers; Immunologics; Immunosuppression; Infection; Inflammation; Inflammatory; Interleukin-17; Kinetics; Laboratories; Lead; Lower Gastrointestinal Tract; Lymphoid Cell; Macaca; Macaca mulatta; Mediating; Mouth Neoplasms; Mucosal Immune Responses; Mucous Membrane; Oral; Oral cavity; Oral mucous membrane structure; Pathogenicity; Periodontitis; Phenotype; Primates; Production; Regulation; Role; SIV; Shapes; Symbiosis; T cell response; Therapeutic; Tissues; Vagina; Viral; antimicrobial; cell type; cytotoxic; gastrointestinal; gastrointestinal epithelium; immune activation; immune function; innovation; interleukin-22; interleukin-23; microbial; microbiome; microbiota; microorganism; novel; oral microbiome; pathogen; probiotic therapy; reproductive; response; secondary infection

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，导致严重的微生物感染。 生态失调和慢性免疫激活，最终推动疾病进展。此外，破坏一个 在HIV诱导的免疫抑制过程中，口腔是研究最少的粘膜环境， 导致念珠菌病、坏死性牙龈炎、牙周炎、毛状白斑、口腔肿瘤增加， 有助于并预测其他部位的远端疾病并发症。RORγt+先天性淋巴样细胞3型（ILC 3） 产生IL-17和IL-22，对维持GI上皮的完整性、介导粘膜炎症和炎症反应至关重要。 抗微生物防御和肠道微生物区系的稳定性，但其他人和我们最近已经显示出大量， 口腔、生殖和胃肠道粘膜中ILC 3数量和功能的系统性改变（Li 和Reeves，Front Immunol，2013; Li等人，PLoS Path，2014）。此外，在我们未发表的初步报告中， 数据显示：1. SIV感染在口腔中诱导高度炎性和细胞毒性ILC 3表型; 2.使用开发的新型ILC 3消耗抗体在口腔、结肠直肠和阴道粘膜中的有效消耗 我们的实验室专门为恒河猴做的。3.特定微生物物种的生态失调与 慢性免疫激活;和4.益生菌疗法减少SIV感染期间的免疫激活， 诱导粘膜中功能性ILC 3数目的扩增。在这个创新和变革的建议中， 我们将评估ILC 3作为粘膜敏感和靶向调节剂的核心假设， 通过三个互补的特定目标，在口腔中实现体内平衡、免疫激活和微生物菌群： 1.通过实验确定ILC在调节口腔微生物组和口腔粘膜中的作用 稳态; 2.定义SIV感染的动力学、活化和详细的免疫学效应， 口腔中的ILC和微生物组;以及3.研究益生菌治疗对口腔ILC的影响 和微生物组之间的关系。