Action of SARS CoV2 in Human Brain Cultures

SARS CoV2 在人脑培养物中的作用

• 批准号: 10173327
• 负责人: VALINA L. DAWSON
• 金额: $ 54.26万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10173327
• 关键词: 2019-nCoV; Acute; Acute respiratory failure; Affect; Age; Alzheimer' s Disease; Amyloid beta-Protein; Astrocytes; Blood Vessels; Blood capillaries; Brain; Brain region; COVID-19; Cardiopulmonary; Cells; Cessation of life; China; Clinical; Confusion; Disease; Drug Targeting; Encephalitis; Event; Future; Gene Expression; Genetic Transcription; Guillain-Barré Syndrome; Headache; Heart failure; Human; Infection; Inflammasome; Inflammation; Injury; Lead; Meningitis; Microglia; Mus; Nausea; Nerve Degeneration; Nervous System Physiology; Nervous system structure; Neuroglia; Neurologic Symptoms; Neurons; Nose; Organoids; Outcome; Parkinson Disease; Pathologic; Patients; Peptidyl-Dipeptidase A; Predisposition; Proteins; Reaction; Reporting; Respiration; Respiratory Signs and Symptoms; Respiratory physiology; Risk Factors; Role; Route; SARS coronavirus; Seizures; Smell Perception; Stroke; Structure of parenchyma of lung; Taste Perception; Testing; Therapeutic; Tissues; Tropism; Unconscious State; Virus; alpha synuclein; brain cell; cell injury; heart function; improved; induced pluripotent stem cell; insight; mind control; misfolded protein; neuron loss; neurotoxicity; programs; relating to nervous system; response; single-cell RNA sequencing; tau Proteins

PROJECT SUMMARY There is emerging evidence that SARS-CoV2 or COVID19 gains entry into human brain cells leading to a sequela of neurologic symptoms. There is concern that SARS-CoV2 may lead to neurotoxicity and that neuronal death in the regions of the brain that control respiration and cardiac function may be a contributing factor to the acute loss of cardio respiratory function and death. SARS-CoV2 could gain access to the brain by several routes including through the nose, or neurons innervating infected lung tissue or through the cells lining blood capillaries in the brain. COVID-19 patients lose their sense of smell or taste often before the onset of respiratory symptoms and a patient presented with Guillain-Barré syndrome before testing positive for SARS- CoV2. It appears that at least 36% of COVID19 patients had neurologic manifestations including headache, nausea, loss of consciousness, strokes, confusion, encephalitis, meningitis and seizures. These clinical observations strongly indicate a role for SARS-CoV2 in the death of neurons and importantly the brain may be one of the first tissues infected and affected. The actions of SARS-CoV2 on the different cells in the brain, as well as the infectivity, tropism, and replication in brain cells is not yet known. In this application we propose to evaluate: (1) The tropism and replication of SARS-CoV2 in human microglia, astrocytes, neurons, and determine relative susceptibility? (2) The mechanisms of cellular injury and evaluate potential protective approaches. (3) Determine the transcriptional responses to SARS CoV2 infection in human neurons, astrocytes, and microglia at the single cell level to gain new insight into the differential response of brain cells to SARS CoV2 to better understand the neural deficits the virus causes.

项目概要 有新的证据表明 SARS-CoV2 或 COVID19 进入人类脑细胞，导致 神经系统症状的后遗症。人们担心 SARS-CoV2 可能会导致神经毒性，并且 控制呼吸和心脏功能的大脑区域的神经元死亡可能是一个促成因素 导致心肺功能急性丧失和死亡的因素。 SARS-CoV2 可以通过以下方式进入大脑： 多种途径，包括通过鼻子或神经元支配受感染的肺组织或通过细胞内壁 大脑中的毛细血管。 COVID-19 患者在发病前经常失去嗅觉或味觉 呼吸道症状和一名在 SARS 检测呈阳性之前出现格林-巴利综合征的患者 冠状病毒2。至少 36% 的新冠肺炎患者出现神经系统症状，包括头痛、 恶心、意识丧失、中风、精神错乱、脑炎、脑膜炎和癫痫发作。这些临床 观察结果强烈表明 SARS-CoV2 在神经元死亡中发挥作用，重要的是大脑可能 最先被感染和受影响的组织之一。 SARS-CoV2 对大脑中不同细胞的作用，如 以及脑细胞中的感染性、趋向性和复制性尚不清楚。在此应用中，我们建议 评估：(1) SARS-CoV2 在人类小胶质细胞、星形胶质细胞、神经元和细胞中的趋向性和复制 确定相对敏感性 ? (2)细胞损伤机制及潜在保护作用评价 接近。 (3)确定人类神经元对SARS CoV2感染的转录反应， 单细胞水平的星形胶质细胞和小胶质细胞，以获得对脑细胞差异反应的新见解 SARS CoV2，以更好地了解该病毒引起的神经缺陷。