Gamma Delta T cell and microbial modulation to target chronic SIV-associated inflammation

Gamma Delta T 细胞和微生物调节靶向慢性 SIV 相关炎症

• 批准号: 10666598
• 负责人: Namita Rout
• 金额: $ 72.49万
• 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: 2022-07-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666598
• 关键词: Affect; Aging; Anti-Inflammatory Agents; Bacteria; Biological Assay; Biological Markers; Biopsy; Cardiovascular Diseases; Cardiovascular system; Cell physiology; Cells; Chronic; Coculture Techniques; Development; Diabetes Mellitus; Disease; Epithelium; Frequencies; Functional disorder; Gene Expression Profile; Genetic Transcription; Goals; Gut Mucosa; HIV; HIV Infections; Health; Hepatic; High Prevalence; Homeostasis; Human; IL17 gene; Immune; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Interleukin-15; Interleukin-2; Intervention; Intestines; Joints; Kidney; Kidney Diseases; Leaky Gut; Link; Liver diseases; Macaca; Maintenance; Malignant Neoplasms; Mediating; Metabolic Diseases; Modeling; Molecular; Mucous Membrane; Neurocognitive Deficit; Outcome; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Process; Reporting; Research; Residual state; Resolution; Risk; Role; SIV; Science; Supplementation; T-Lymphocyte; Testing; Therapeutic Effect; Treponema; Viral; Viral Load result; Virus Diseases; Zoledronate; age related; antiretroviral therapy; bisphosphonate; clinical development; combinatorial; comorbidity; cytokine; dysbiosis; experience; fecal transplantation; gastrointestinal epithelium; gut homeostasis; gut microbes; gut microbiome; immune activation; immune function; immunoregulation; improved; in vivo; inflammatory marker; interleukin-22; intestinal epithelium; microbial; microbiome; nonhuman primate; novel; prevent; repaired; simian human immunodeficiency virus; systemic inflammatory response; transcriptome sequencing; γδ T cells

PROJECT SUMMARY Gut dysfunction, dysbiosis, and residual inflammation are major factors contributing to the high prevalence of comorbidities such as metabolic, cardiovascular, kidney, and liver diseases in people living with HIV under antiretroviral therapy (ART). However, the immune mechanisms underlying the process of gut dysfunction and persistent inflammation in the setting of long-term viral suppression with ART remain poorly understood. We have recently reported in the nonhuman primate model of HIV with ART that following initial resolution of circulating leaky gut biomarkers during early ART, dysregulation of IL-17/IL-22 functions of intestinal Gamma delta (γδ) T cells are correlated with resurgence of intestinal epithelial barrier damage (IEBD) and systemic inflammation during long-term ART. Further, intestinal Vδ2T cell frequencies significantly correlated with the loss of specific gut microbial species during long-term ART. Based on this, we propose to test the hypothesis that specific dysregulation of the IL-17/IL-22 pathway in γδT cells, particularly the Vδ2 subset, contributes to breakdown of the gut epithelial barrier, resulting in microbial translocation (MT) and systemic inflammation during chronic treated HIV infection. Here, we propose to assess the role of Vδ2 γδT cells in the repair and maintenance of gut homeostasis through a direct in vivo intervention. We will evaluate the effect of in vivo Vδ2T-stimulation and expansion on IEBD, MT, and inflammation in long-term ART suppressed SIV-infection via treatment with the aminobisphosphonate drug, Zoledronate (ZOL) in combination with IL-2 and IL-15 cytokines. Second, we propose to test the hypothesis that modulation of gut microbiome during chronic SIV+ART with microbial supplementation combined with in vivo Vδ2T cell stimulation will have a synergistic effect on improving gut barrier functions. We will administer fecal microbial transplant (FMT) supplemented with anti-inflammatory bacterial species, with/without ZOL treatment to assess normalization of systemic inflammatory markers and gut immune functions in FMT-only vs. FMT with immunomodulation. Finally, we will determine the mechanisms by which γδT cells and microbiome modulate intestinal epithelial homeostasis during long-term treated SIV infection. We will longitudinally assess the transcriptional and functional signatures of intestinal IL-17/IL-22 producing cells and evaluate epithelial barrier functions in precisely timed gut biopsies and in vitro coculture assays to identify novel cellular/molecular mechanisms involved. By exploring the beneficial effects of combined immune/microbiome modulation on epithelial barrier-protective function and systemic inflammation, this study will have the critical impact of opening new avenues for the continued development of combinatorial approaches to target enteropathy and chronic inflammation in people living with HIV.

项目摘要 肠道功能障碍，营养不良和残留炎症是导致高患病率的主要因素 在艾滋病毒下生HIV患者的合并症，例如代谢，心血管，肾脏和肝脏疾病 抗逆转录病毒疗法（ART）。但是，肠道功能障碍过程和 在与艺术的长期病毒抑制环境中，持续的炎症仍然很众所周知。我们 最近在非人类的艾滋病毒私人模型中报告了ART 早期艺术期间循环泄漏的肠道生物标志物，IL-17/IL-22肠伽玛功能的失调 Delta（γδ）T细胞与肠上皮屏障损伤（IEBD）和全身性的复苏相关 长期艺术期间的炎症。此外，肠道Vδ2T细胞频率与损失显着相关 长期艺术期间特定的肠道微生物物种基于此，我们建议检验以下假设。 γδT细胞中IL-17/IL-22途径的特异性失调，尤其是VΔ2子集，有助于 肠道上皮屏障的崩溃，导致微生物易位（MT）和全身注射 慢性治疗的HIV感染。在这里，我们建议评估Vδ2γδT细胞在修复和维护中的作用 通过直接的体内干预进行肠道稳态。我们将评估体内Vδ2T刺激的效果 以及对长期ART的IEBD，MT和注射的扩展，通过使用 氨基膦酸酯药物，唑来济酸酯（ZOL）与IL-2和IL-15细胞因子结合使用。第二，我们 提议测试以下假设，即在慢性SIV+ART中使用微生物调节肠道微生物组 补充与体内Vδ2T细胞刺激相结合将对改善肠道屏障具有协同作用 功能。我们将管理补充抗炎细菌的粪便微生物移植（FMT） 物种，进行/不进行ZOL处理以评估全身炎症标记和肠道免疫的归一化 具有免疫调节的仅限FMT与FMT的功能。最后，我们将确定γδT的机制 细胞和微生物组在长期治疗的SIV感染期间调节肠上皮稳态。我们将 纵向评估肠道IL-17/IL-22产生细胞的转录和功能特征 评估精确定时的肠击活检和体外共培养测定中的上皮屏障功能以识别新型 涉及细胞/分子机制。通过探索联合免疫/微生物组的有益作用 对上皮屏障保护功能和全身注射的调节，本研究将具有关键 开放新途径的影响，以持续开发组合方法 艾滋病毒患者的肠病和慢性炎症。