Blood brain barrier integrity and immune dynamics contributing to neuropsychiatric sequela in COVID long-haulers

血脑屏障完整性和免疫动态导致新冠长途运输者的神经精神后遗症

基本信息

批准号：
10688300
负责人：
Leah Helane Rubin
金额：
$ 290.64万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10688300
关键词：
Acute Address Alzheimer&apos s Disease Anhedonia Anxiety Area Attention Biological Markers Blood Blood - brain barrier anatomy Brain Brain imaging Brain-Derived Neurotrophic Factor CCL2 gene CD14 gene COVID-19 long hauler CX3CL1 gene CXCL10 gene CXCR3 gene Cell Surface Proteins Cells Central Nervous System Chronic Cognition Cognitive Control Groups Data Depressed mood Disease Encephalopathies Endothelium FCGR3B gene Fractalkine Functional disorder Funding HIV Headache Health IL18 gene Image Imaging Techniques Immune Immunophenotyping Individual Infection Infiltration Inflammation Inflammatory Infrastructure Interleukin-6 Link Long COVID Magnetic Resonance Imaging Measures Memory Mental Health Moods National Institute of Mental Health Neuroimmunomodulation Neurologic Neurologic Symptoms Neurons Neuropathy Patients Peripheral Blood Mononuclear Cell Phase Research Research Personnel Role SARS-CoV-2 infection Seizures Stroke Surface Symptoms TNF gene Techniques Testing Therapeutic Vascular Endothelial Growth Factors Virus Virus Diseases Water acute infection arterial spin labeling blood-brain barrier disruption blood-brain barrier permeabilization cell motility chemokine cognitive neuroscience coronavirus disease cytokine depressive symptoms experience innovation interest migration mild cognitive impairment monocyte multidisciplinary neuroAIDS neuroimmunology neuroinflammation neuropsychiatric sequelae of COVID-19 neuropsychiatric symptom neuropsychiatry novel perceived stress psychologic response rumination small molecule therapeutic development trafficking

项目摘要

PROJECT SUMMARY/ABSTRACT A substantial (>35%) proportion of patients acutely infected with SARS-CoV-2 demonstrate neurological symptoms ranging from serious headaches to encephalopathy, stroke, seizure, and acute neuropathies. However, some patients experience lingering or emergent neuropsychiatric symptoms within weeks to months following acute infection. The neuropsychiatric burden among COVID long-haulers is a major issue; and yet the underlying pathophysiology of these conditions remains elusive. SARS-Cov-2 infection results in increased levels of circulating proinflammatory cytokines/chemokines and elevation of intermediate monocyte (CD14+CD16+) subsets in blood. Trafficking of these proinflammatory monocytes into the brain of individuals with other chronic viral infections (eg. HIV) has emerged a putative contributor to neuroinflammation, blood brain barrier (BBB) disruption and may explain the ongoing neurological sequalae in COVID long-haulers. We propose to test our hypothesis that COVID long-haulers will have BBB disruption mechanistically linked to targeted, circulating proinflammatory cytokines/chemokines and elevation of intermediate monocytes that traffic to the brain. Monocyte infiltration in response to infection is a hallmark of CNS inflammation and occurs consistently in chronic conditions. Thus, we further hypothesize that disruption in BBB integrity by intermediate monocyte activation and diapedesis promotes persistent neuroinflammation and altered neuronal activity, contributing to neuropsychiatric sequela COVID-19 long-haulers. To this end, we propose cross-sectional imaging to assess BBB integrity, with neuropsychiatric assessments, and immunophenotyping in 100 COVID long-haulers and 100 individuals who have recovered from acute COVID (control group). First, we aim to assess BBB integrity in COVID long-haulers (vs. control) and its contribution to neuropsychiatric conditions. We will assess BBB integrity using a novel, non-contrast magnetic resonance imaging technique that uses water-extraction-with-phase- contrast-arterial-spin-tagging (WEPCAST), to determine BBB permeability to small molecules. We have shown this to be sensitive to BBB change in mild cognitive impairment, a precursor to Alzheimer’s disease, and are currently using this technique in other neuro-infectious diseases. Second, we aim to assess the link between circulating soluble markers, PBMC-associated markers, and BBB permeability to small molecules, which collectively may promote diapedesis into brain. We target factors implicated in transmigration of activated PBMCs across the BBB into brain, where they may contribute to neuronal damage and neuropsychiatric burden in COVID long-haulers. After 3 years of funding, this R01 will advance our understanding of BBB integrity and related PBMC migration into the brains of COVID long-haulers, which may contribute to neuroinflammation and related neuropsychiatric burden. Findings will inform next steps in the development of therapeutic approaches to minimize PBMC contribution to neuroinflammation in COVID long-haulers.

项目概要/摘要很大一部分 (>35%) 急性感染 SARS-CoV-2 的患者表现出神经系统症状症状包括严重头痛、脑病、中风、癫痫发作和急性神经病。然而，一些患者会在数周至数月内出现持续或突发的神经精神症状急性感染后，新冠肺炎长途运输者的神经精神负担是一个主要问题；这些疾病的潜在病理生理学仍然难以捉摸，SARS-Cov-2 感染会导致增加。循环促炎细胞因子/趋化因子的水平和中间单核细胞的升高血液中的 (CD14+CD16+) 亚群将这些促炎性单核细胞贩运到患有此病的个体的大脑中。其他慢性病毒感染（例如艾滋病毒）已被认为是导致神经炎症、血脑我们建议，BBB 障碍可能会解释新冠肺炎长途运输者中持续存在的神经系统后遗症。检验我们的假设，即新冠肺炎长途运输车将 BBB 破坏与目标、循环促炎细胞因子/趋化因子和运输到的中间单核细胞的升高感染引起的单核细胞浸润是中枢神经系统炎症的标志，并且持续发生在大脑中。因此，我们进一步研究了中间单核细胞对血脑屏障完整性的破坏。激活和血渗促进持续的神经炎症和神经活动，有助于为此，我们建议采用横断面成像来评估 COVID-19 的神经精神后遗症。 100 名新冠长途运输者和 100 名新冠肺炎患者的 BBB 完整性、神经精神评估和免疫表型分析首先，我们的目标是评估从急性新冠肺炎中康复的个体的 BBB 完整性。 COVID 长途运输者（与对照）及其对神经精神疾病的影响我们将评估 BBB 完整性。使用一种新颖的非对比磁共振成像技术，该技术使用相萃取水对比动脉自旋标记 (WEPCAST)，用于确定 BBB 对小分子的渗透性。这对轻度认知障碍（阿尔茨海默病的前兆）的 BBB 变化敏感，并且目前，该技术已用于其他神经感染性疾病的治疗。其次，我们的目的是评估两者之间的联系。循环可溶性标记物、PBMC 相关标记物以及 BBB 对小分子的通透性，我们的目标是与激活的迁移有关的因素。 PBMC 穿过血脑屏障进入大脑，可能会造成神经元损伤和神经精神负担经过 3 年的资助，这款 R01 将增进我们对 BBB 完整性和的理解。相关的 PBMC 迁移到新冠病毒长途运输者的大脑中，这可能会导致神经炎症和相关的神经精神负担的研究结果将为下一步开发治疗方法提供信息。最大限度地减少 PBMC 对新冠肺炎长途运输者神经炎症的影响。