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.

项目摘要 抗逆转录病毒疗法（ART）已经导致了一个范式的转变，从艾滋病毒感染是一种致命的疾病， 可控制的慢性病。然而，艾滋病毒感染者（PWH）受到不完全免疫的困扰， 恢复，增加肠道功能障碍，残留炎症，非感染性 合并症，如代谢、心血管、肾脏和肝脏疾病。考虑到肠道 上皮屏障损伤（IEBD）和微生物易位（MT）驱动HIV相关炎症， 慢性炎症与PWH中的非感染性合并症之间的联系，更好地了解肠道- 介导的免疫机制是IEBD过程和长期治疗HIV期间炎症的基础 感染是关键。我们的初步研究证明了先天性gdT细胞和先天性类胶质瘤细胞之间的协同作用， SIV-猕猴模型中长期cART期间细胞3型（ILC 3）功能障碍。此外，我们最近报道， Vd 2 gdT细胞的上皮屏障保护性IL-17/IL-22功能的丧失可能有助于IEBD和MT 并在长期SIV-ART过程中导致全身炎症。基于此，我们建议验证这一假设 Vd 2 gdT细胞和ILC 3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MT和全身炎症，在慢性HIV感染期间， 为了这个目标，我们的目标是纵向评估转录和免疫表型 Vd 2 T和ILC 3细胞的特征，并通过以下方法评估胃肠道不同部分的肠道屏障功能： SIV感染的长期ART疗程。第二，我们将检验Vd 2 T的体内激活 细胞将恢复肠道屏障的完整性，并通过增强的IL-17/IL-18， 22功能。为此，我们将给予Vd 2 T刺激性氨基二膦酸盐药物唑仑膦酸盐， 与IL-2和IL-15细胞因子组合施用到ART处理的SIV感染的猕猴用于体内扩增， 增强Vd 2 T细胞中的IL-17/IL-22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Vd 2 T和ILC 3亚群的功能特征， IEBD/MT标记物、炎症和微生态失调在辅助生殖治疗的PWH中的作用。 确定Vd 2 T细胞和ILC 3中IL-17/IL-22通路失调的机制，以及它们在 在ART有效抑制病毒期间，肠道屏障损伤、微生态失调和HIV/SIV感染的炎症， 和（B）确定Vd 2 gdT细胞对上皮屏障功能和微生物稳态的贡献。 鉴定关键的先天性IL-17/IL-22产生细胞在肠损伤修复/丧失中所起的作用 体内平衡可能对肠病和炎性共病的治疗有重要影响 在威尔斯亲王医院。