Innate immune mechanisms of epithelial barrier disruption during treated HIV and SIV infections

HIV 和 SIV 感染治疗期间上皮屏障破坏的先天免疫机制

• 批准号: 10668086
• 负责人: Namita Rout
• 金额: $ 55.48万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10668086
• 关键词: Animal Model; Automobile Driving; Cardiovascular Diseases; Cells; Chronic; Chronic Disease; Clinical Management; Clinical Pathways; Development; Diabetes Mellitus; Disease; Epithelial; Functional disorder; Gastrointestinal tract structure; Genetic Transcription; Goals; HIV; HIV Enteropathy; HIV Infections; HIV antiretroviral; HIV therapy; High Prevalence; Homeostasis; Immune; Immune response; Immunotherapeutic agent; Immunotherapy; Infection; Inflammation; Inflammatory; Interleukin-15; Interleukin-17; Interleukin-2; Intervention; Intestinal permeability; Intestines; Kidney; Kidney Diseases; Link; Liver diseases; Lymphoid Cell; Macaca; Maintenance; Mediating; Metabolic Diseases; Modeling; Outcome; Pathway interactions; Patients; Peripheral; Persons; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Play; Process; Production; Reporting; Research; Residual state; Risk; Role; SIV; Sampling; Sensitivity Training Groups; Sentinel; Signal Transduction; T-Lymphocyte; Testing; Tight Junctions; Viral; Viral Cytopathogenic Effect; Viral Physiology; Work; antiretroviral therapy; base; bisphosphonate; cell type; comorbidity; cytokine; dysbiosis; effective intervention; enteric infection; gastrointestinal epithelium; gut dysbiosis; gut microbiome; gut microbiota; high risk; in vivo; in vivo Model; inflammatory marker; innate immune mechanisms; insight; interleukin-22; intestinal epithelium; intestinal homeostasis; microbial; multidisciplinary; novel; prevent; repaired; restoration; synergism; systemic inflammatory response; translational model; γδ T cells

PROJECT SUMMARY Antiretroviral therapy (ART) has led to a paradigm shift from HIV infection being a fatal disease to a manageable chronic illness. People living with HIV (PWH), however, are plagued with incomplete immune restoration, increased intestinal dysfunction, residual inflammation, and high prevalence of non-infectious comorbidities such as metabolic, cardiovascular, kidney, and liver diseases. Given the evidence of intestinal epithelial barrier damage (IEBD) and microbial translocation (MT) driving HIV-associated inflammation, and the link between chronic inflammation and non-infectious comorbidities in PWH, better understanding of the gut- mediated immune mechanisms underlying the process of IEBD and inflammation during long-term treated HIV infection is critical. Our preliminary studies demonstrate a synergy between innate gdT cells and Innate Lymphoid Cell type 3 (ILC3) dysfunction during long-term cART in the SIV-macaque model. Further, we recently reported that a loss in epithelial barrier protective IL-17/IL-22 functions of Vd2 gdT cells may contribute to IEBD and MT and resultant systemic inflammation during long-term SIV-ART. Based on this, we propose to test the hypothesis that specific dysregulation of IL-17/IL-22 pathway in Vd2 gdT cells and ILC3 leads to breakdown of tight junctions of the gut epithelial barrier, resulting in MT and systemic inflammation during chronic HIV infection with long- term ART. Toward this goal, we aim to longitudinally assess the transcriptional and immunophenotypic signatures of Vd2T and ILC3 cells and evaluate gut barrier functions in different sections of the GI tract through the course of long-term ART in SIV infection. Second, we will test the hypothesis that in vivo activation of Vd2T cells will restore gut barrier integrity and reduce inflammation during long-term SIV-ART via enhanced IL-17/IL- 22 function. Toward this, we will administer the Vd2T-stimulating amino-bisphosphonate drug, Zolendronate, in combination with IL-2 and IL-15 cytokines to ART-treated SIV-infected macaques for in vivo expansion and enhanced IL-17/IL-22 function in Vd2T cells and evaluate the beneficial effect on IEBD, MT and inflammation. Finally, we propose to identify functional signatures of peripheral Vd2T and ILC3 subsets associated with plasma IEBD/MT markers, inflammation, and dysbiosis in PWH on ART. The goals of this multi-disciplinary study are to identify the mechanisms of dysregulation of IL-17/IL-22 pathway in Vd2T cells and ILC3, and their causal role in gut barrier damage, dysbiosis, and inflammation of HIV/SIV-infection during effective viral suppression with ART, and to (b) determine the contribution of Vd2 gdT cells to epithelial barrier functions and microbial homeostasis. Identification of the role played by key innate IL-17/IL-22 producing cells in the repair/loss of intestinal homeostasis is likely to have a critical impact on the management of enteropathy and inflammatory comorbidities in PWH.

项目概要 抗逆转录病毒疗法 (ART) 已导致艾滋病毒感染从致命疾病转变为致命疾病的范式转变。 可控制的慢性疾病。然而，艾滋病毒感染者 (PWH) 却受到不完全免疫的困扰 恢复、肠道功能障碍增加、残留炎症和非感染性患病率高 代谢、心血管、肾脏和肝脏疾病等合并症。鉴于肠道证据 上皮屏障损伤 (IEBD) 和微生物易位 (MT) 驱动 HIV 相关炎症，以及 PWH 中慢性炎症与非感染性合并症之间的联系，更好地了解肠道 长期治疗 HIV 期间 IEBD 和炎症过程中介导的免疫机制 感染至关重要。我们的初步研究证明了先天性 gdT 细胞和先天性淋巴细胞之间的协同作用 SIV-猕猴模型中长期 cART 期间的 3 型细胞 (ILC3) 功能障碍。此外，我们最近报道 Vd2 gdT 细胞上皮屏障保护性 IL-17/IL-22 功能的丧失可能导致 IEBD 和 MT 以及长期 SIV-ART 期间由此产生的全身炎症。基于此，我们建议检验假设 Vd2 gdT 细胞和 ILC3 中 IL-17/IL-22 通路的特异性失调导致紧密连接的破坏 肠道上皮屏障的破坏，导致长期 HIV 感染期间的 MT 和全身炎症 术语“艺术”。为了实现这一目标，我们的目标是纵向评估转录和免疫表型 Vd2T 和 ILC3 细胞的特征，并通过以下方式评估胃肠道不同部分的肠道屏障功能 SIV 感染的长期 ART 过程。其次，我们将检验 Vd2T 体内激活的假设 在长期 SIV-ART 期间，细胞将通过增强的 IL-17/IL- 恢复肠道屏障完整性并减少炎症 22个功能。为此，我们将使用 Vd2T 刺激氨基二膦酸盐药物 Zolendronate 与 IL-2 和 IL-15 细胞因子组合，对经 ART 处理的 SIV 感染的猕猴进行体内扩增和 增强 Vd2T 细胞中 IL-17/IL-22 的功能，并评估对 IEBD、MT 和炎症的有益作用。 最后，我们建议识别与血浆相关的外周 Vd2T 和 ILC3 子集的功能特征 接受 ART 治疗的 PWH 中的 IEBD/MT 标记物、炎症和生态失调。这项多学科研究的目标是 确定 Vd2T 细胞和 ILC3 中 IL-17/IL-22 通路失调的机制及其在 在使用 ART 有效抑制病毒期间，肠道屏障受损、菌群失调和 HIV/SIV 感染炎症， (b) 确定 Vd2 gdT 细胞对上皮屏障功能和微生物稳态的贡献。 鉴定关键先天性 IL-17/IL-22 产生细胞在肠道修复/丧失中所起的作用 体内平衡可能对肠病和炎症合并症的治疗产生关键影响 在战后卫生院。