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

项目概要/摘要 粘膜相关不变T细胞（MAIT）是非常规、先天性样T细胞的一个子集，它们高度表达 在粘膜组织和外周血中含量丰富，并识别微生物维生素B2（核黄素）代谢产物 从各种各样的微生物。此外，MAIT细胞最近已被证明具有组织修复功能， 功能协调发展的在HIV感染中，MAIT细胞在血液和肠道中不可逆转地丢失，剩余的细胞显示 激活迹象增加，功能电位降低。艾滋病的另一个后果是 肠道微生物组的生态失调，其特征在于重新塑造的肠道微生物丰度变成了致病性的。艾滋病毒- 相关的受损肠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，即使在有效的ART治疗的个体中也是如此。研究表明， 慢性HIV感染与肠道细菌多样性减少和梭菌富集有关， 与减少的T细胞计数和更高的炎症有关。然而，艾滋病毒感染中生态失调的病因 仍不清楚我们有一个前所未有的机会来解决这一重大的知识差距， 利用匹配的肠道组织活检和外周血单核细胞（PBMC）的生物标本， 入组观察性研究的初治和ART治疗的急性和慢性HIV感染者 泰国艾滋病研究。由于与肠道完整性和微生物感染的控制有关， MAIT细胞在HIV-1感染中的功能障碍可能会使宿主的粘膜和抗微生物能力减弱， 免疫力到目前为止，还没有研究将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微生物群的特定组成。该项目的总体目标是： 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 （B）确定在急性HIV感染早期开始的ART是否改变了HIV感染的免疫功能。 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 车厢在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HIV感染者的样本与未感染HIV的健康对照相匹配 年龄和性别。我们将研究易位梭菌的增加是否与MAIT的变化有关 血液和肠道中的细胞数量和活化。我们将研究HIV诱导的MAIT细胞功能障碍是否是 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， ART启动时间对微生物生态失调和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 这两个目标，我们将确定肠道菌群和致病性肠道菌群是否调节了肠道菌群的数量、表型， 外周和肠道MAIT细胞在HIV感染中的功能。

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.