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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：
10458248
负责人：
Shelli Farhadian
金额：
$ 7.06万
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/10458248
关键词：
2019-nCoV ACE2 Affect Anosmia Antibodies Ataxia Attenuated Autopsy Biology Blood Blood Circulation 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 Infections Cerebrospinal Fluid China 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 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 infections Maps Measurement Mediating Modeling Monitor Mus Nervous System Trauma Nervous system structure Neuraxis 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 Tumor-infiltrating immune cells 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 immunoreaction influenzavirus insight interest monocyte mortality mouse model nervous system disorder neuroinflammation neuron loss neuropathology neurotropic novel 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.

项目总结