Determining the interplay of MAIT cells and the translocated microbiome in HIV-induced neuroinflammation

确定 MAIT 细胞和易位微生物组在 HIV 诱导的神经炎症中的相互作用

• 批准号: 10744475
• 负责人: Michael Jay Corley
• 金额: $ 49.3万
• 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: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744475
• 关键词: Animals; Astrocytes; Autopsy; Binding; Biological Response Modifiers; Blood; Brain; Cell Communication; Cell Degranulation; Cells; Central Nervous System; Central Nervous System Infections; Cerebrospinal Fluid; Chronic; Clinical; Colon; Cryopreservation; Data; Environment; Functional disorder; Gut Mucosa; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Human; Immune; Immunologics; Immunotherapy; Impaired cognition; Infection; Interruption; Intervention; Intestines; Lead; Ligands; Liquid substance; Lymphocyte; Maintenance; Mediating; Mediator; Meninges; Microbe; Microglia; Modeling; Mucous Membrane; Neuroimmune; Neurons; Neuropathogenesis; Pathogenesis; Peripheral Blood Mononuclear Cell; Persons; Phase; Plasma; Riboflavin; Sampling; T cell receptor repertoire sequencing; T-Cell Activation; T-Lymphocyte; T-cell receptor repertoire; Therapeutic; Tissue Sample; Tissues; Viral; Viremia; acute infection; antimicrobial; brain cell; brain tissue; cell type; chronic infection; comorbidity; dysbiosis; experience; functional disability; gut bacteria; gut dysbiosis; gut homeostasis; gut microbiome; gut-brain axis; immune activation; microbial; microbiome; nervous system disorder; neuroinflammation; neuron loss; nonhuman primate; recruit; simian human immunodeficiency virus; success; trafficking; transcriptome sequencing

Summary/Abstract Significant progress in the treatment of HIV with suppressive ART has led to long term viral suppression; however, people living with HIV (PLWH) continue to experience CNS perturbations including HIV-associated neurocognitive disorders (HAND). Persistent CNS immune activation is a hallmark of HIV neuropathogenesis, and persists even in PLWH who are on suppressive ART. The identification of persistent intestinal dysbiosis in people living with HIV (PLWH) and ongoing neurological disorders despite ART has highlighted the importance of gut–brain communication in the pathogenesis of central nervous system (CNS) co-morbidities in PLWH. However, the question regarding the identity of immunological, microbial, and central nervous system components responsible for this crosstalk remains unclear. Our studies of mucosal-associated invariant T cells (MAIT cells), which are innate-like T cells able to recognize conserved bacterial ligands presented by MHC- related 1 (MR1) molecule, during HIV-1 infection have shown that MAIT cells are activated early during infection and expand in blood and colonic mucosa coincident with peak viremia, in a manner associated with emerging microbial translocation. Moreover, preliminary single cell transcriptomic and TCR sequencing data from our group has detected a large proportion of MAIT cells in cerebrospinal fluid (CSF) of PLWH, suggesting MAIT cells may serve as immune mediator of the gut-brain axis. Yet, a MAIT cell immune mediated gut-brain axis mechanism has not been studied in HIV infection. We hypothesize that MAIT cells are a major immune cell type that mediate the crosstalk between gut dysbiosis, microbial translocation, immune cell dysfunction, and CNS co- morbidities in PLWH. To comprehensively study MAIT cells across compartments including the CNS, we will leverage already collected biospecimens of gut, cryopreserved peripheral blood mononuclear cells, plasma, CSF fluid, cryopreserved CSF cell pellets, and postmortem brain tissues samples from a previous non-human primate study conducted by MHRP using SHIV-1157ipd3N4. In Aim 1, we will longitudinally compare and contrast the relationship between the gut microbiome to the MAIT cells residing in CSF, blood, gut, and brain during SHIV infection, post ART, and following analytical treatment interruption. In aim 2, we will determine the effects of translocated microbiome upon MAIT-neural cell interactions. Overall, the findings from this R21 proposal could open new immunotherapy avenues for PLWH with neurological disorders despite virological suppression by ART by targeting MAIT cells as one of the key immune mediators of the gut-brain axis.

摘要/摘要 抑制ART的艾滋病毒治疗方面的重大进展已导致长期抑制病毒。 但是，患有艾滋病毒（PLWH）的人继续经历中枢神经系统扰动 神经认知障碍（手）。持续的CNS免疫激活是HIV神经病发生的标志， 甚至在PLWH中仍然存在抑制艺术。识别持续性肠道营养不良 患有艾滋病毒（PLWH）和正在进行的神经系统疾病目的地艺术的人们强调了重要性 肠道神经系统发病机理（CNS）合并症中肠道 - 脑通信的合并症。 但是，有关免疫，微生物和中枢神经系统的身份的问题 负责此串扰的组件尚不清楚。我们对粘膜相关不变T细胞的研究 （MAIT细胞），它们是先天的T细胞，可以识别由MHC-提出的保守细菌配体 相关1（MR1）分子，在HIV-1感染期间表明Mait细胞在感染期间早期激活 并以与新兴的方式相关的血液和结肠粘膜与峰值病毒血症一致 微生物易位。此外，来自我们的初步单细胞转录组和TCR测序数据 组检测到PLWH的脑脊液（CSF）中的大部分Mait细胞，表明MAIT细胞 可以用作肠脑轴的免疫介质。然而，Mait细胞免疫介导的肠脑轴 机理尚未研究HIV感染。我们假设MAIT细胞是主要的免疫细胞类型 介导肠道营养不良，微生物易位，免疫细胞功能障碍和CNS共同的串扰 PLWH中的病态。为了全面研究包括CNS在内的隔室的MAIT细胞，我们将 杠杆已经收集了肠道，冷冻保存的外周血单核细胞，血浆，CSF 来自以前非人类私有 MHRP使用SHIV-1157IPD3N4进行的研究。在AIM 1中，我们将纵向比较和对比 SHIV期间，肠道微生物组与位于CSF，血液，肠道和大脑中的MAIT细胞之间的关系 在AIM 2中，我们将确定 在Mait神经细胞相互作用上易位的微生物组。总体而言，该R21提案的发现可能 开放新的PLWH的新免疫疗法途径，神经系统疾病目的地抑制ART的病毒学抑制 通过将MAIT细胞作为肠道轴的关键免疫介质之一。