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

• 批准号: 10661769
• 负责人: Michael Jay Corley
• 金额: $ 21.31万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661769
• 关键词: Acute; Address; Age; Anti-Bacterial Agents; Anus; Bacteria; Bacterial Infections; Biological Assay; Biopsy; Blood; CD14 gene; Cell Compartmentation; Cell Count; Cell physiology; Cells; Characteristics; Chronic; Colon; 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; Shapes; Sterility; Swab; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Thailand; Therapeutically Targetable; 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; microbial products; 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; tissue repair

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.

项目摘要 /摘要 粘膜相关的不变T细胞（MAIT）是非常规的，先天性T细胞的子集，它们高度高 富含粘膜组织和外周血，并识别微生物维生素B2（核黄素）代谢物 来自广泛的微生物。此外，最近已证明Mait细胞具有组织修复 功能。在HIV感染中，Mait细胞在血液和肠道中不可逆转地损失，其余细胞显示 功能潜力降低的激活迹象升高。艾滋病毒的另一个结果是一个深刻的 肠道微生物组的营养不良，其特征在于共同体的重塑抽象变为致病性。艾滋病病毒- 相关造成的肠粘膜免疫学被认为是持续免疫学激活的主要驱动力， 病毒复制，发病率和死亡率，即使在有效艺术的个体中也是如此。研究表明 慢性HIV感染与肠道细菌的多样性降低和融合细菌的富集有关， 与T细胞计数减少和感染较高有关。然而，HIV感染中营养不良的病因 仍然不清楚。我们有一个前所未有的机会，可以通过 利用肠道组织活检和外周血单核细胞（PBMC）的匹配的生物测量 幼稚和艺术治疗的急性和慢性艾滋病毒感染的人参加了检查 泰国的艾滋病毒研究。由于与肠道完整性和微生物感染的控制有关 HIV-1感染中MAIT细胞功能障碍可能会使宿主患有粘膜和抗菌素弱的宿主 免疫。迄今为止，尚无研究将Mait细胞与肠道完整性，微生物易位或 HIV感染期间肠道组织中菌群的特异性构成。该项目的总体目标是：（a） 确定正常肠道菌群中的失衡是否影响MAIT细胞频率，表型和组织修复 跨HIV感染阶段的功能； （b）确定在急性HIV感染早期开始的艺术是否改变了 肠道菌群的初始扰动与Mait细胞的早期参与之间的关系 车厢。在AIM 1中，我们将对匹配的PBMC和等离子体进行MAIT细胞和微生物组分析 来自治疗幼稚的急性HIV感染的个体的样本和与HIV未感染的健康对照相匹配的样本 年龄和性别。我们将检查易旋转杆菌的增加是否与MAIT的变化有关 细胞数量和血液中的激活。我们将研究HIV诱导的MAIT细胞功能障碍是 与降低肠道屏障完整性的标记有关。在AIM 2中，我们将使用PBMC和等离子体样本 未感染和HIV感染的个体，在急性感染的不同阶段开始治疗以评估 艺术启动时间对微生物营养不良和MAIT细胞组织修复功能的影响。体外 将进行实验以研究梭菌对MAIT细胞功能障碍的影响。通过调查 这两个目的我们将确定共生和致病性肠道微生物群是否调整数量，表型和 HIV感染中外周和肠道细胞的功能。