Impact of Microbial Dysbiosis on MAIT Cell Tissue Repair Program after Acute HIV Infection

急性 HIV 感染后微生物失调对 MAIT 细胞组织修复程序的影响

基本信息

批准号：
10481899
负责人：
Michael Jay Corley
金额：
$ 25.69万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
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：
2022-07-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10481899
关键词：
Acute Address Age Anaerobic Bacteria Anti-Bacterial Agents Anus Bacteria Bacterial Infections Biological Assay Biopsy Blood CD14 gene Cell Compartmentation Cell Count Cell physiology Cells Characteristics Chronic Complementarity Determining Regions Complex Consequences of HIV Cryopreservation Diagnosis Disease Enrollment Enteral Equilibrium Etiology Frequencies Functional disorder Fusobacteria Gender Goals Gut Mucosa HIV HIV Infections HIV-1 Immune System Diseases Immune system Immunity Immunologics Impaired wound healing In Vitro Individual Infection Inflammation Knowledge Ligands Link Maintenance Medical Research Methods Microbe Military Personnel Morbidity - disease rate Mucosal Immunity Mucous Membrane Outcome Participant Pathogenicity Peripheral Peripheral Blood Mononuclear Cell Persons Phenotype Plasma Play Proteobacteria Reading Research Riboflavin Role Sampling Sepsis Sterility Swab T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Technology Testing Thailand Time Tissues Viremia Virus Replication acute infection antimicrobial cell type chronic infection cohort dysbiosis experimental study functional disability gut dysbiosis gut health gut homeostasis gut microbiome gut microbiota host microbiota immune activation microbial microbial community microbial composition microbiome microbiome analysis microbiome composition microbiome research microbiota mortality novel strategies pathogen peripheral blood programmed cell death protein 1 programs rRNA Genes repair function stool sample therapeutic target tissue repair

项目摘要

Project Summary / Abstract Mucosa-associated invariant T-cells (MAIT) are a subset of unconventional, innate-like T cells that are highly abundant in mucosal tissues and peripheral blood and recognize microbial vitamin B2 (riboflavin) metabolites from a wide range of microbes. Furthermore, MAIT cells have been recently shown to have tissue repair functions. In HIV infection, MAIT cells are irreversibly lost in the blood and gut, and remaining cells display elevated signs of activation with decreased functional potential. Another consequence of HIV is a profound dysbiosis of the gut microbiome characterized by reshaped abundances of commensals turned pathogenic. HIV- associated compromised gut mucosal immunity is thought to be a major driver of persistent immune activation, viral replication, and morbidity and mortality, even in individuals who are on effective ART. Studies show that chronic HIV infection is associated with reduced gut bacterial diversity and an enrichment in fusobacteria, associated with reduced T cell counts and higher inflammation. Yet, the etiology of dysbiosis in HIV infection remains unclear. We have an unprecedented opportunity to address this significant gap in knowledge by leveraging matched biospecimens of gut tissue biopsies and peripheral blood mononuclear cells (PBMCs) from treatment naïve and ART-treated acutely and chronically HIV infected individuals enrolled in an observational HIV study in Thailand. Because of associations with gut integrity and control of microbial infections, the dysfunction of MAIT cells in HIV-1 infection may leave the host with weakened mucosal and antimicrobial immunity. To date, no studies have linked MAIT cells with surrogates of gut integrity, microbial translocation, or specific makeup of the microbiota in gut tissue during HIV infection. The overall goals of the project are to: (a) determine if imbalance in the normal gut microbiota impacts MAIT cell frequency, phenotype, and tissue repair function across stages of HIV infection; and (b) to ascertain if ART initiated early in acute HIV infection alters the relationship between the initial perturbations of the gut microbiota and the early engagement of the MAIT cell compartment. In AIM 1, we will perform MAIT cell and microbiome analysis on matched PBMCs and plasma samples from treatment naïve acutely HIV infected individuals, and HIV uninfected healthy controls matched for age and gender. We will examine if increases in translocated fusobacteria are associated with change in MAIT cells numbers and activation in the blood and gut. We will investigate if HIV-induced dysfunction of MAIT cells is associated with markers of reduced gut barrier integrity. In AIM 2, we will use PBMCs and plasma samples from uninfected and HIV-infected individuals that initiated treatment at different stages of acute infection to evaluate the impact of ART initiation timing on microbial dysbiosis and MAIT cell tissue repair functions. In vitro experiments will be performed to study the impact of fusobacteria on MAIT cell dysfunction. By investigating these two aims we will determine if commensal and pathogenic gut microbiota tune the number, phenotype, and functions of peripheral and gut MAIT cells in HIV infection.

项目概要/摘要粘膜相关不变 T 细胞 (MAIT) 是非常规、先天性 T 细胞的一个子集，具有高度粘膜组织和外周血中含量丰富，可识别微生物维生素 B2（核黄素）代谢物此外，MAIT 细胞最近被证明具有组织修复功能。在 HIV 感染中，MAIT 细胞在血液和肠道中不可逆地丢失，而剩余的细胞则表现出来。激活迹象增加而功能潜力降低。艾滋病毒的另一个后果是深远的。肠道微生物群失调，其特征是大量共生菌被重塑，转而致病。相关的肠道粘膜免疫被认为是持续免疫激活的主要驱动力，病毒复制、发病率和死亡率，即使是在接受有效抗逆转录病毒疗法的个体中。慢性艾滋病毒感染与肠道细菌多样性减少和梭杆菌富集有关，然而，HIV 感染中菌群失调的病因与 T 细胞数量减少和炎症增加有关。我们有一个前所未有的机会来解决这一巨大的知识差距。利用肠道组织活检和外周血单核细胞 (PBMC) 的匹配生物样本参加观察性研究的未接受治疗和接受过 ART 治疗的急性和慢性感染者泰国的艾滋病毒研究由于与肠道完整性和微生物感染控制有关， HIV-1 感染中 MAIT 细胞的功能障碍可能会使宿主的粘膜和抗菌能力减弱迄今为止，还没有研究将 MAIT 细胞与肠道完整性、微生物易位或免疫的替代物联系起来。 HIV 感染期间肠道组织中微生物群的具体组成该项目的总体目标是：(a) 确定正常肠道微生物群的不平衡是否会影响 MAIT 细胞频率、表型和组织修复 HIV 感染各个阶段的功能；以及 (b) 确定在急性 HIV 感染早期开始的 ART 是否会改变肠道微生物群的初始扰动与 MAIT 细胞的早期参与之间的关系在 AIM 1 中，我们将对匹配的 PBMC 和血浆进行 MAIT 细胞和微生物组分析。来自未经治疗的急性艾滋病毒感染者和未感染艾滋病毒的健康对照的样本匹配我们将检查易位梭菌的增加是否与 MAIT 的变化相关。我们将研究 HIV 诱导的 MAIT 细胞功能障碍是否与血液和肠道中的细胞数量和激活有关。与肠道屏障完整性降低的标志物相关。在 AIM 2 中，我们将使用来自 PBMC 和血浆样本。在急性感染的不同阶段开始治疗的未感染者和 HIV 感染者进行评估 ART 启动时间对微生物失调和 MAIT 细胞组织修复功能的影响。将通过调查研究梭杆菌对 MAIT 细胞功能障碍的影响。这两个目标我们将确定共生和致病性肠道微生物群是否调节数量、表型和外周和肠道 MAIT 细胞在 HIV 感染中的功能。