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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：
10672911
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/10672911
关键词：
2019-nCoV ACE2 Affect Anosmia Antibodies Ataxia Attenuated Autopsy Biology Blood Brain Brain Stem COVID-19 COVID-19 diagnosis COVID-19 impact COVID-19 pandemic COVID-19 patient COVID-19 treatment Cardiopulmonary Case Series Cells Central Nervous System Central Nervous System Infections Cerebrospinal Fluid China Circulation Communities Coronavirus Data Disease Dose Encephalopathies Enrollment Europe Evaluation Family member Fever Flow Cytometry Functional disorder Genomics Goals Headache Health Heart Heart Hypertrophy Histology Histopathology Hospitalization Human Hypertension Hypogeusia Hypoxemia Immune Immune response Impairment Individual Infection Inflammatory Inflammatory Response Institutional Review Boards Intractable Headaches Invaded Investigation Knockout Mice Lung Lung infections Maps Measurement Mediating Modeling Monitor Mus Nervous System Nervous System Trauma Neurologic Neurologic Effect Neurologic Symptoms Neurological Models Neurons Neurotropism Olfactory dysfunction 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 Disease Respiratory Failure Respiratory Tract Infections Role SARS coronavirus SARS-CoV-2 infection Sampling Secondary to Seizures Smell Perception Spinal Puncture Stains Structure of parenchyma of lung Study models Supporting Cell Symptoms Taste Perception Tissues Toxic effect Validation Viral Virus Wild Type Mouse adeno-associated viral vector antigen detection associated symptom biobank brain tissue central nervous system injury common symptom coronavirus disease cytokine detection assay human tissue immune cell infiltrate immunoreaction influenzavirus insight interest monocyte mortality mouse model nervous system disorder neuroinflammation neuron loss neuropathology neurotropic novel novel coronavirus overexpression patient subsets pulmonary symptom receptor respiratory response single-cell RNA sequencing success viral detection

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.

项目概要 COVID-19 大流行严重影响了世界人口，并对世界造成了持久影响全球社会的经济、健康和心理。尽管它与 SARS-CoV-1 有相似之处，但完整的 SARS-CoV-2 引起的病理生理学程度尚不清楚。特别是肺外表现 SARS-CoV-2 感染的影响仍知之甚少。来自中国和欧洲的系列案例表明中枢神经系统参与了至少一部分患者的疾病过程，有一些报告估计高达 30% 的 COVID-19 患者出现神经系统症状，包括癫痫发作、顽固性症状头痛，嗅觉和味觉受损。尽管有报道称 COVID-19 存在神经系统疾病对于患者来说，尚不清楚 SARS-CoV-2 是否侵入中枢神经系统 (CNS)。其他研究冠状病毒，包括 SARS-CoV-1，表现出明显的神经趋向性和神经炎症与该病毒家族的其他成员有关。这些研究提出了 SARS-CoV-2 的可能性可能通过侵入中枢神经系统或通过炎症增加引起神经系统症状中枢神经系统内的细胞因子。我们假设 SARS-CoV-2 感染具有神经侵袭潜力并导致感染者中枢神经系统内免疫状态的改变和过度炎症。我们进一步假设中枢神经系统感染通过表达 ACE2 的直接毒性加剧呼吸功能障碍神经元是心肺功能的关键调节因子。我们的调查将结合以下力量人类研究利用小鼠模型，我们可以很容易地管理病毒并评估病理生理学。目标 1，我们将确定 COVID-19 患者的中枢神经系统免疫反应神经系统症状。结合使用单细胞 RNA 测序、细胞因子分析、病毒分析测序和抗体验证，我们将全面剖析中枢神经系统内的炎症反应与 COVID-19 患者的体循环进行比较。使用鼠标模型，在目标 2 中，我们将研究 SARS-CoV-2 的脑炎潜力。使用几种互补的方法用SARS-CoV-2感染小鼠，我们将病毒引入小鼠的中枢神经系统。使用耗竭抗体和各种基因敲除小鼠，我们将确定哪些免疫细胞是必需的通过生存研究、流式细胞术和免疫荧光染色对这些小鼠的神经病理学进行研究。最后，在目标 3 中，我们将评估中枢神经系统感染对呼吸系统结局的影响。因为众所周知 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，我们怀疑中枢神经系统感染 SARS-CoV-2 会加剧 SARS-CoV-2 呼吸道疾病。这三个目标将有助于支持我们关于 SARS-CoV-2 感染如何影响中枢神经系统和中枢神经系统的假设。呼吸室。我们期望我们的研究结果将揭示治疗确诊患者的新策略与 COVID-19 相关，有助于获得了解 SARS-CoV-2 病理生理学生物学的新见解。