Amphiregulin-Immunometabolism axis in oral immunity and inflammation during HIV infection

HIV感染期间口腔免疫和炎症中的双调蛋白-免疫代谢轴

基本信息

批准号：
10480271
负责人：
Pushpa Pandiyan
金额：
$ 68.52万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10480271
关键词：
Address Age Aging Amphiregulin Attenuated Bioinformatics Biopsy CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell physiology Cells Clinical Clinical Immunology Data Dentistry Diagnosis FOXP3 gene Feedback Flow Cytometry Functional disorder Fungal DNA Gingiva Goals HIV HIV Infections Health Human Human Papillomavirus Hypoxia IRAK1 gene Immune Immune System Diseases Immune response Immune system In Vitro Individual Inflammasome Inflammation Inflammatory Interleukin-1 beta Intervention Lead Ligands Ligation Light Link Literature Lymphoid Lymphoid Tissue Measurement Mediating Metabolic Mouth Diseases Mucosal Immunity Mucous Membrane Oral Oral Medicine Oral cavity Oral mucous membrane structure Organoids Pathway interactions Persons Proteins Proto-Oncogene Proteins c-akt RNA Regulatory T-Lymphocyte Residual state Role SYK gene Saliva Salivary Signal Pathway Signal Transduction Site Smoking T-Lymphocyte TLR2 gene Testing Tissues Tonsil Up-Regulation Viral reservoir Work antiretroviral therapy clinical practice co-infection comorbidity dectin 1 dysbiosis gut microbiome immune health immunoregulation in vivo inflammatory milieu insight metabolome microbiome microbiome analysis microbiome composition microbiota mortality multidisciplinary novel oral fungal oral immunity oral microbiome oral tissue programmed cell death protein 1 programs receptor single-cell RNA sequencing systemic inflammatory response transcriptomics

项目摘要

ABSTRACT Systemic inﬂammation and mortality in people living with HIV (PLWH) are associated with mucosal immune dysfunction and persistent viral reservoirs in the mucosa and lymphoid tissues. In the previous project period, we have demonstrated the role of CD4+ FOXP3+regulatory T cells (Treg) dysregulation in contributing to aging- and HIV-associated oral inﬂammation. The dysfunctional Tregs that we uncovered in the oral mucosa of PLWH mimic tissue-resident CD4+ T cells expressing high levels of PD-1 and amphiregulin (AREG). These cells correlate with CD38+HLADR+ CD4+T cell hyperactivation and dysfunction, toll-like receptor 2 (TLR-2), and inﬂammasome/IL-1β signaling in vivo, and require IL-1β/AKT pathways for their expansion in the context of HIV infection. Here we propose to address the role of oral fungal dysbiosis in establishing the inﬂammatory environment and triggering oral immune cells to become dysfunctional. Building on our more recent results from salivary metabolome analysis in PLWH, we will examine the underlying pathways at the interface of dectin-1, AREG, inﬂammasome, and immunometabolism signaling pathways in three well-connected aims. Thus, our proposal will reveal new directions to manage oral immune-dysfunction and thereby systemic inﬂammation, and alter current clinical practice.

抽象的 HIV 感染者 (PLWH) 的全身炎症和死亡率与粘膜相关免疫功能障碍和粘膜和淋巴组织中的持续病毒库。项目期间，我们证明了 CD4+ FOXP3+ 调节性 T 细胞 (Treg) 失调在我们在研究中发现的功能失调的 Tregs 会导致与衰老和 HIV 相关的口腔炎症。 PLWH 口腔粘膜模拟组织驻留 CD4+ T 细胞，表达高水平 PD-1 和双调蛋白 (AREG)。这些细胞与 CD38+HLADR+ CD4+T 细胞过度激活和功能障碍相关，类似于 Toll。受体 2 (TLR-2) 和体内炎症小体/IL-1β 信号转导，并且需要 IL-1β/AKT 途径来发挥作用在此，我们建议探讨口腔真菌失调在艾滋病毒感染中的作用。建立炎症环境并引发口腔免疫细胞功能失调。根据我们对 PLWH 唾液代谢组分析的最新结果，我们将检查潜在的 dectin-1、AREG、炎症小体和免疫代谢信号通路界面的通路因此，我们的建议将揭示管理口腔免疫功能障碍的新方向。从而引起全身炎症，并改变当前的临床实践。