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: 10548685
• 负责人: Namita Rout
• 金额: $ 71.6万
• 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/10548685
• 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; Epithelial; Frequencies; Functional disorder; Gene Expression Profile; Genetic Transcription; Goals; Gut Mucosa; HIV; HIV Infections; Health; Hepatic; High Prevalence; Homeostasis; Human; Immune; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Interleukin-15; Interleukin-17; 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; Testing; Therapeutic Effect; Treponema; Viral; Viral Load result; Virus Diseases; Zoledronate; age related; antiretroviral therapy; base; 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.

项目概要 肠道功能障碍、菌群失调和残留炎症是导致肠道菌群高患病率的主要因素 艾滋病毒感染者的合并症，如代谢、心血管、肾脏和肝脏疾病 然而，抗逆转录病毒治疗（ART）是肠道功能障碍过程中的免疫机制。 我们对 ART 长期病毒抑制背景下的持续炎症仍知之甚少。 最近报道，在采用 ART 的非人类灵长类动物艾滋病毒模型中，在初步解决 早期 ART 期间循环漏肠生物标志物、肠道 Gamma 的 IL-17/IL-22 功能失调 δ (γδ) T 细胞与肠上皮屏障损伤 (IEBD) 和全身性损伤的复发相关 此外，长期 ART 期间的炎症，肠道 Vδ2T 细胞频率与损失显着相关。 基于此，我们建议检验以下假设： γδT 细胞（特别是 Vδ2 子集）中 IL-17/IL-22 通路的特异性失调有助于 肠道上皮屏障的破坏，导致微生物易位（MT）和全身炎症 在这里，我们建议评估 Vδ2 γδT 细胞在修复和维持中的作用。 我们将评估体内 Vδ2T 刺激的效果。 以及长期 ART 中 IEBD、MT 和炎症的扩展，通过治疗抑制 SIV 感染 其次，我们将氨基二磷酸盐药物唑来膦酸 (ZOL) 与 IL-2 和 IL-15 细胞因子结合使用。 提议检验以下假设：慢性 SIV+ART 期间微生物对肠道微生物组的调节 补充与体内Vδ2T细胞刺激相结合将对改善肠道屏障产生协同作用 我们将进行粪便微生物移植（FMT）并辅以抗炎细菌。 物种，有/没有 ZOL 治疗，以评估全身炎症标志物和肠道免疫的正常化 仅 FMT 与免疫调节 FMT 中的功能最后，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。 纵向评估肠道 IL-17/IL-22 产生细胞的转录和功能特征 在精确定时的肠道活检和体外共培养测定中评估上皮屏障功能，以识别新的 通过探索联合免疫/微生物组的有益作用。 上皮屏障保护功能和全身炎症的调节，这项研究将具有关键意义 为持续发展目标组合方法开辟新途径的影响 艾滋病毒感染者的肠病和慢性炎症。