How the Novel Coronavirus Attacks the Brain

新型冠状病毒如何攻击大脑

• 批准号: 10450852
• 负责人: Maura Boldrini
• 金额: $ 11.35万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-14 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450852
• 关键词: 2019-nCoV; Acute; Affect; Age; Alzheimer' s disease pathology; Anosmia; Anterior; Astrocytes; Attention; Behavioral; Blood Vessels; Brain; Brain Injuries; Brain Pathology; Brain region; Brodmann' s area; COVID-19; COVID-19 impact; COVID-19 patient; Calcium Binding; Calcium ion; Cell Nucleus; Cells; Clinical; Coagulation Process; Cognitive; Comprehension; Computerized Medical Record; Confusion; Coronavirus; Data; Dendrites; Diffuse; Dysautonomias; Endothelial Cells; Endothelium; Evaluation; Event; Family; Fatigue; Follow-Up Studies; Gene Expression; Genes; Genomics; Growth Factor; Headache; Hippocampus (Brain); Hospitals; Human; ITGAM gene; Immunohistochemistry; Impaired cognition; Impairment; Infection; Inflammation; Inflammatory; Injury; Institution; Intake; Interleukin Suppression; Interleukin-1; Interleukin-10; Interleukin-6; Investigation; Lead; Length; Link; Maps; Memory; Microglia; Modeling; Molecular; Nasal cavity; Nasopharynx; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurologic Effect; Neurologic Symptoms; Neurons; Pathologic; Patients; Peptide Hydrolases; Pericytes; Persons; Pharmaceutical Preparations; Phenotype; Pilot Projects; Prefrontal Cortex; Process; Proteins; Recording of previous events; Rest; Role; Running; SARS-CoV-2 infection; SARS-CoV-2 negative; Serum; Short-Term Memory; Sleeplessness; Smell Perception; Societies; Suicide; Symptoms; System; TNF gene; Testing; Therapeutic Effect; Thinness; Time; Tissues; Viral; Viral Load result; base; brain fog; brain tissue; cell injury; chemokine; cognitive function; coronavirus disease; cost; cytokine; cytokine release syndrome; density; differential expression; executive function; improved; inflammatory marker; insight; mRNA Expression; mental state; neurofilament; neuroinflammation; neuropathology; neuropsychiatric symptom; neuropsychiatry; novel coronavirus; receptor; sex; spatial relationship; transcriptome; transcriptome sequencing; 2019-nCoV; Acute; Affect; Age; Alzheimer' s disease pathology; Anosmia; Anterior; Astrocytes; Attention; Behavioral; Blood Vessels; Brain; Brain Injuries; Brain Pathology; Brain region; Brodmann' s area; COVID-19; COVID-19 impact; COVID-19 patient; Calcium Binding; Calcium ion; Cell Nucleus; Cells; Clinical; Coagulation Process; Cognitive; Comprehension; Computerized Medical Record; Confusion; Coronavirus; Data; Dendrites; Diffuse; Dysautonomias; Endothelial Cells; Endothelium; Evaluation; Event; Family; Fatigue; Follow-Up Studies; Gene Expression; Genes; Genomics; Growth Factor; Headache; Hippocampus (Brain); Hospitals; Human; ITGAM gene; Immunohistochemistry; Impaired cognition; Impairment; Infection; Inflammation; Inflammatory; Injury; Institution; Intake; Interleukin Suppression; Interleukin-1; Interleukin-10; Interleukin-6; Investigation; Lead; Length; Link; Maps; Memory; Microglia; Modeling; Molecular; Nasal cavity; Nasopharynx; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurologic Effect; Neurologic Symptoms; Neurons; Pathologic; Patients; Peptide Hydrolases; Pericytes; Persons; Pharmaceutical Preparations; Phenotype; Pilot Projects; Prefrontal Cortex; Process; Proteins; Recording of previous events; Rest; Role; Running; SARS-CoV-2 infection; SARS-CoV-2 negative; Serum; Short-Term Memory; Sleeplessness; Smell Perception; Societies; Suicide; Symptoms; System; TNF gene; Testing; Therapeutic Effect; Thinness; Time; Tissues; Viral; Viral Load result; base; brain fog; brain tissue; cell injury; chemokine; cognitive function; coronavirus disease; cost; cytokine; cytokine release syndrome; density; differential expression; executive function; improved; inflammatory marker; insight; mRNA Expression; mental state; neurofilament; neuroinflammation; neuropathology; neuropsychiatric symptom; neuropsychiatry; novel coronavirus; receptor; sex; spatial relationship; transcriptome; transcriptome sequencing

Presentations of patients infected with SARS-CoV-2 are varied and unique in their neurological manifestations, including loss of smell, confusion, and altered mental status, when the course of the novel coronavirus disease (COVID-19) is complicated by insults to the neurological system. The nasopharynx and nasal cavities are reservoirs for high viral load and olfactory tissue contains key receptors and proteases that may facilitate viral entry and replication at the cellular level. Downstream mechanisms of brain cellular invasion and integration remain poorly understood, particularly how SARS-CoV-2 may be instigating diffuse neurological effects. Patients with COVID-19 sustain a severe cytokine storm, the interplay between inflammation and coagulation combined with endothelial damage, may lead to thrombo-embolic events, and microglia activation leading to neuronal damage. Patients also present with long-term brain sequela of COVID-19, including “brain fog,” difficulties concentrating, impaired short-term and working memory, fatigue, headache, dysautonomia, and insomnia, and the neuropathological bases of these symptoms are unknown. Appropriate evaluation of specific brain regions from deceased patients with COVID-19 who did and did not present with neurological symptoms will allow for improved comprehension of possible targets to limit brain damage. Additionally, lessons from how SARS-CoV-2 affects the brain may provide insight into generalizable mechanisms for effects of neuroinflammation on neurodegenerative diseases. We aim to determine: 1. Whether COVID-19 patients with neurological presentations at the time of intake (NP-COVs) have altered brain expression of genes regulating inflammation and coagulation compared to those without (COVs) and non-COVID-19 age and sex matched controls (CONT). We will map the whole transcriptome in the entire brain tissue section using single nuclei RNA sequencing (sn-RNA-seq, 10X Genomics). We will validate and quantify candidate mRNAs expression on neurons, glia, and vasculature-associated cells, using Duplex RNAscope® (ACDBio), as we successfully performed in CONT. 2. Whether NP-COVs have elevated brain pro-inflammatory markers. We will run a Human Cytokine/Chemokine/Growth Factor Panel (48 Plex Kit, Milliopre) and quantify cytokines, chemokines and growth factors. We will map their expression on neurons and glia, using double immunohistochemistry (IHC), as we piloted in CONT. 3. If NP-COVs have elevated brain microglia activation. Using double-IHC for microglia markers TSPO (translocator protein), CD11b, Iba1 (Ionized calcium binding adaptor molecule), and neuronal markers, and stereology for cell quantification, we will compute activated (amoeboid) and resting (small cell body and elaborated thin processes) microglia, and map spatial relationship to neurons. 4. If NP-COVs have reduced neuronal density and dendrite arborization. Using double-IHC for neuronal marker NeuN and neurofilament, Stereoinvestigator and Neurolucida (MBF Inc.), will quantify neuron density, dendrite length and arborization, as in our pilot studies.

感染SARS-COV-2的患者的演示在其神经学中是独特的 当小说的过程 对神经系统的侮辱使冠状病毒病（COVID-19）变得复杂。鼻咽和 鼻腔咖啡馆是高病毒载荷和嗅觉组织的依据，其中包含关键的受体和蛋白酶 可能有助于在细胞水平上促进病毒进入和复制。脑细胞的下游机制 入侵和整合仍然很少了解，尤其是SARS-COV-2如何促进扩散 神经效应。 COVID-19患者维持严重的细胞因子风暴，这是 炎症和凝结结合内皮损伤，可能导致势头 - 发散事件，并且 小胶质细胞激活导致神经元损伤。患者还出现长期的大脑后遗症 COVID-19，包括“脑雾”，困难集中，短期和工作记忆障碍，疲劳， 这些符号的头痛，功能障碍和失眠以及这些符号的神经病理基础是未知的。 适当评估来自死者Covid-19患者的特定大脑区域，他们做过，没有 出现神经系统症状将可以改善对可能限制大脑的可能目标的理解 损害。此外，从SARS-COV-2影响大脑的方式中，经验教训可以提供对可推广的洞察力 神经炎症对神经退行性疾病的影响的机制。我们旨在确定： 1。摄入时神经系统介绍患者（NP-COV）是否有所改变 与没有（COV）和没有（COV）和的基因相比 非旋转19岁的年龄和性匹配的对照（续）。我们将在整个中绘制整个转录组 使用单核RNA测序（SN-RNA-Seq，10x基因组学）的脑组织截面。我们将验证并 使用双链体量化神经元，神经胶质和脉管系统相关细胞上的候选mRNA表达 RNASCOPE®（ACDBIO），正如我们在CONT中成功执行的那样。 2。np-cov是否大脑升高 促炎性标记。我们将运行人类细胞因子/趋化因子/生长因子面板（48个PLEX试剂盒， 毫米）和量化细胞因子，趋化因子和生长因子。我们将在神经元上绘制它们的表达 和Glia，使用双重免疫组织化学（IHC），如我们在cont中的试验。 3。如果NP-COV升高 脑小胶质细胞激活。使用双IIHC进行小胶质细胞标记TSPO（转运蛋白），CD11b，IBA1 （电离钙结合衔接子分子）和神经元标记物以及用于细胞定量的立体学，我们 将计算激活（变形虫）和静止（小细胞体和详细过程）的小胶质细胞，以及 地图与神经元的空间关系。 4。如果NP-COV降低了神经元的密度和树突木化。 使用Double-IHC进行神经元标记NEUN和NEURILAMENT，立体评估器和Neurolucida（MBF） Inc.），如我们的初步研究，将量化神经元密度，树突长度和树博化。