Viral and immune-mediated CNS pathology during SARS-CoV-2 infection

SARS-CoV-2 感染期间病毒和免疫介导的中枢神经系统病理学

基本信息

批准号：
10160327
负责人：
Shelli Farhadian
金额：
$ 41.78万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-24 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10160327
关键词：
2019-nCoV Affect Antibodies Ataxia Attenuated Autopsy Biological Assay Biology Blood Blood Circulation Brain Brain Stem COVID-19 COVID-19 pandemic Cardiopulmonary Case Series Cells Central Nervous System Infections Cerebrospinal Fluid China Communities Coronavirus Data Detection Diagnosis Disease Dose Encephalopathies Enrollment Europe Evaluation Family member Fever Flow Cytometry Functional disorder Genomics Goals Headache Health Heart Heart Hypertrophy Histology Histopathology Human Hypertension Hypogeusia Hypoxemia Immune Immune response Impairment Individual Infection Inflammatory Inflammatory Response Institutional Review Boards Intractable Headaches Invaded Investigation Knockout Mice Lead Lung Lung diseases Lung infections Maps Measurement Mediating Modeling Monitor Mus Nervous System Trauma Nervous system structure Neuraxis Neurologic Neurologic Effect Neurologic Symptoms Neurological Models Neurons Neurotropism Outcome Pathogenicity Pathology Pathway interactions Patients Physiological Plaque Assay Plasma Cells Pneumonia Population Process Production Protocols documentation Pulmonary Heart Disease Pulmonary Pathology Reporting Respiration Disorders Respiratory Failure Respiratory Signs and Symptoms Respiratory Tract Infections Role SARS coronavirus Sampling Secondary to Seizures Smell Perception Spinal Puncture Stains Structure of parenchyma of lung Study models Supporting Cell Symptoms Taste Perception Tissues Toxic effect Tumor-infiltrating immune cells Validation Viral Viral Antigens Virus Wild Type Mouse adeno-associated viral vector associated symptom biobank brain tissue central nervous system injury common symptom coronavirus disease cytokine human tissue immunoreaction influenzavirus insight interest monocyte mortality mouse model nervous system disorder neuroinflammation neuron loss neuropathology neurotropic novel overexpression patient subsets receptor respiratory response single-cell RNA sequencing success

项目摘要

Project Summary The COVID-19 pandemic has rampantly affected the population of the world and created lasting effects on the economy, health and psyche of the global community. Although it shares similarities with SARS-CoV-1, the full extent of the pathophysiology caused by SARS-CoV-2 is unclear. In particular, extrapulmonary manifestations effects of SARS-CoV-2 infection remain poorly understood. Case series from China and Europe suggest that the central nervous system is involved in the disease process in at least a subset of patients, with some reports estimating up to 30% of COVID-19 patients having neurological symptoms, including seizure, intractable headache, and impaired smell and taste. Although there are reports of neurological disease in in COVID-19 patients, it is unclear if SARS-CoV-2 invades the central nervous system (CNS). Studies of other coronaviruses, including SARS-CoV-1, demonstrate clear neurotropism as well as neuroinflammation associated with other members of this family of viruses. These studies raise the possibility that SARS-CoV-2 may cause neurological symptoms either through invasion of the CNS or through an increase in inflammatory cytokines within the CNS. We hypothesize that SARS-CoV-2 infections have neuroinvasive potential and lead to altered and hyperinflammatory immune states within the CNS of infected individuals. We further hypothesize that infection of the CNS exacerbates respiratory dysfunction through direct toxicity of ACE2 expressing neurons that are critical regulators of cardiopulmonary function. Our investigations will combine the power of human studies with those utilizing mouse models in which we can readily administer virus and assess for pathophysiology. Aim 1, we will determine the CNS immune responses in COVID-19 patients with neurological symptoms. Using a combination of single cell RNA-sequencing, cytokine profiling, viral sequencing and antibody validations, we will fully dissect out the inflammatory responses within the CNS compartment compared to the systemic circulation in COVID-19 patients. Using mouse models, in Aim 2, we will investigate the encephalitic potential of SARS-CoV-2. Using several complementary approaches to infect mice with SARS-CoV-2, we will introduce the virus into the central nervous system of mice. Using depletion antibodies and various knockout mice, we will identify which immune cells are required for neuropathology in these mice through survival studies, flow cytometry and immunofluorescent staining. Finally, in Aim 3, we will evaluate the effects of CNS infection on respiratory outcomes. Because of the known expression of ACE2 in the brainstem, and the brainstem’s critical role in regulating cardiopulmonary functions, we suspect that CNS infection with SARS-CoV-2 will exacerbate SARS-CoV-2 respiratory disease. These three aims will help support our hypotheses of how SARS-CoV-2 infections can affect the CNS and respiratory compartments. We expect that our findings will uncover new strategies to treat patients diagnosed with COVID-19 and help gain new insight to understanding the biology of SARS-CoV-2 pathophysiology.

项目摘要 19009年大流行对世界产生了巨大影响，并对世界产生了持久影响全球社区的经济，健康和心理。 SARS-COV-2引起的病理生理学的程度尤其不清楚。 SARS-COV-2感染的影响仍然很差。中枢神经系统参与了一部分患者的疾病过程过程，其中一些报告估计多达30％的Covid-19患者有神经系统症状，癫痫发作，棘手头痛，气味和味道受损。患者尚不清楚SARS-COV-2是否在中心神经系统（CNS）中进行了研究冠状病毒（包括SARS-COV-1）表现出清晰的神经性和神经炎症与该病毒家族的其他成员有关。可能会通过中枢神经系统的发明或炎症增加而引起神经系统症状中枢神经系统中的细胞因子。为了改变感染个体的中枢神经系统中的超炎物免疫状态中枢神经系统的感染通过表达ACE2的直接毒性加剧了呼吸功能障碍神经元是心肺功能的关键调节剂。通过那些小鼠模型进行的人类研究，我可以准备就绪，并评估病毒并评估病理生理学。神经症状，使用单细胞RNA的结合，细胞因子分析，病毒测序和抗体验证，我们将充分显示中枢神经系统内的炎症反应与Covid-19患者的全身性循环相比，在AIM 2中，我们将使用sars-cov-2的脑潜力。用SARS-COV-2感染小鼠，我们将将病毒引入小鼠中心神经系统。部署抗体和各种淘汰小鼠，我们将确定需要哪些Imune单元这些小鼠的神经病理通过生存研究，流式细胞仪和免疫荧光袭击。在AIM 3中，我们将评估CNS感染对呼吸结局的评估。 ACE2在脑干中的表达，以及脑干在调节心肺功能中的关键作用，我们怀疑使用SARS-COV-2感染的中枢神经系统感染会加剧SARS-COV-2呼吸疾病。三个目标将有助于支持我们的假设，即SARS-COV-2感染如何影响中枢神经系统和呼吸道隔室。借助Covid-19，并有助于获得新的见解，以理解SARS-COV-2病理生理学的生物学。