Cytokine-mediated neurologic disease in COVID-19

COVID-19 中细胞因子介导的神经系统疾病

基本信息

批准号：
10704594
负责人：
Abigail Rose Vanderheiden
金额：
$ 7.22万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10704594
关键词：
2019-nCoV Acute Address Anosmia Anxiety Astrocytes Attention Attentional deficit Autopsy Behavior Control Behavioral Blood - brain barrier anatomy Blood brain barrier dysfunction Body Weight decreased Brain Brain region C57BL/6 Mouse COVID-19 COVID-19 pathogenesis COVID-19 patient Cells Central Nervous System Cognition Cognitive deficits Communicable Diseases Coronavirus Coughing Cre-LoxP Data Defect Endothelial Cells Fatigue Fever Follow-Up Studies Generations Hamsters Headache Hemorrhage Hippocampus Human Hypoxia IL1R1 gene Immune Immune response Immune signaling Immunohistochemistry Immunologics Impaired cognition In Vitro Individual Infarction Infection Inflammation Inflammatory Inflammatory Response Injury Interleukin-1 Interleukin-1 beta Ischemia Learning LoxP-flanked allele Lung Mediating Memory Memory impairment Microglia Modeling Movement Disorders Mus Nervous System Trauma Neuroimmunomodulation Neurologic Dysfunctions Neurologic Symptoms Neurons Nodule Patients Peripheral Pharmacological Treatment Production Psychoses Recovery Reporting Resolution Respiratory Disease Respiratory System Role SARS-CoV-2 B.1.351 SARS-CoV-2 infection Sampling Signal Induction Signal Pathway Signal Transduction Source Specimen Surveys Symptoms Synapses Syndrome Testing Tight Junctions Tissues Variant Viral Load result Virus Diseases abstracting attentional control axon injury behavior test betacoronavirus blood-brain barrier disruption blood-brain barrier permeabilization brain endothelial cell cytokine excitatory neuron executive function experimental study glial activation immune activation inducible Cre insight mouse model nerve stem cell nervous system disorder neural correlate neurogenesis neuroimaging neuroinflammation neurotoxic novel novel coronavirus pandemic disease post SARS-CoV-2 infection receptor recruit response severe COVID-19 spatial memory stem cell differentiation synaptogenesis

项目摘要

PROJECT SUMMARY The newly emerged coronavirus, SARS-CoV-2, has caused a historic pandemic of respiratory disease (COVID- 19). One surprising finding, is that both mild and severe COVID-19 is associated with persistent neurological symptoms, even after resolution of infection. Patients present with a variety of symptoms, from deficits in attention, planning, and other executive functions, to memory impairment, or new psychoses. Post-mortem analyses of brains from individuals with COVID-19 did not find evidence of infectious SARS-CoV-2 in the parenchyma. However, COVID-19 infection is associated with an array of neurological injury, including infarcts, ischemia, hemorrhages, and hypoxia. Immunohistochemistry on post-mortem specimens demonstrated that SARS-CoV-2 infection is associated with blood-brain barrier (BBB) disruption, elevated levels of the pro- inflammatory cytokine, IL-1β, and microglial activation and nodules, and neuronophagia. In other neurovirulent viral infections, IL-1β promotes inflammation in the central nervous system via disruption of the blood-brain barrier and recruitment of immune cells that activate microglia, which eliminate synapses in the hippocampus, a brain region critical for learning and memory. During recovery, IL-1β inhibits neurogenesis, which limits synapse recovery, and induces spatial memory defects. We hypothesize that IL-1β production in the brain during SARS- CoV-2 infection potentiates neurological dysfunction by disrupting the BBB and promoting cognitive and memory deficits. To investigate this, we will use a C57Bl/6 mouse model of COVID-19, in which mice are intranasally infected with B.1.351 (Beta variant), which naturally infects mice. In Aim 1, we will investigate the role of IL-1R1 signaling on BBB disruption using a brain microvascular endothelial cell (BMEC) specific inducible Cre crossed to IL-1R floxed mice. We will also determine if IL-1R1 signaling promotes activation of BMECs and the induction of inflammation. In Aim 2, we will explore if IL-1R1 signaling impacts cognition and memory via inhibition of neurogenesis within ongoing synapse elimination. First, we will determine the impact of IL-1R1 on neurogenesis during infection with B.1.351 using neural stem cell (NSC) specific, inducible Cre mice crossed to IL-1R floxed mice. Next, we test the role of IL-1R1 signaling on recovery of the hippocampal trisynaptic cirucuit via NSC- specific or microglial-specific Cre-IL-1R1 floxed mice. Last, using the same mice as the previous experiment, we will perform behavioral tests on mice recovered from B.1.351 to examine the functional impact of IL-1R1 signaling. Together, in this proposal we will explore the immunological mechanisms that underlie neurological dysfunction during COVID-19.

项目概要新出现的冠状病毒 SARS-CoV-2 引起了历史性的呼吸道疾病大流行 (COVID-19)。 19) 一项令人惊讶的发现是，轻度和重度 COVID-19 都与持续性神经系统疾病有关。症状，即使在感染消退后，患者也会因缺乏功能而出现各种症状。注意力、计划和其他执行功能，记忆障碍或新的精神病。对 COVID-19 患者大脑的分析没有发现感染性 SARS-CoV-2 的证据然而，COVID-19 感染与一系列神经损伤有关，包括梗死、尸检标本的缺血、出血和缺氧。 SARS-CoV-2 感染与血脑屏障 (BBB) 破坏、亲细胞水平升高有关。炎症细胞因子、IL-1β、小胶质细胞激活和结节，以及其他神经毒力中的神经吞噬。病毒感染时，IL-1β 通过破坏血脑促进中枢神经系统炎症屏障和招募激活小胶质细胞的免疫细胞，消除海马体中的突触，对学习和记忆至关重要的大脑区域在恢复过程中，IL-1β 会抑制神经发生，从而限制突触。我们捕获了 SARS 期间大脑中 IL-1β 的产生。 CoV-2 感染通过破坏血脑屏障并促进认知和记忆来加剧神经功能障碍为了研究这一缺陷，我们将使用 COVID-19 的 C57Bl/6 小鼠模型，其中小鼠经鼻注射。感染 B.1.351（Beta 变体），该病毒自然感染小鼠。在目标 1 中，我们将研究 IL-1R1 的作用。使用脑微血管内皮细胞 (BMEC) 特异性诱导型 Cre 杂交对 BBB 破坏发出信号我们还将确定 IL-1R1 信号传导是否促进 BMEC 的激活和诱导。在目标 2 中，我们将探讨 IL-1R1 信号传导是否通过抑制炎症影响认知和记忆。持续突触消除过程中的神经发生首先，我们将确定 IL-1R1 对神经发生的影响。在感染 B.1.351 期间，使用神经干细胞 (NSC) 特异性、可诱导的 Cre 小鼠与 IL-1R floxed 杂交接下来，我们通过 NSC- 测试 IL-1R1 信号传导对海马三突触回路恢复的作用。最后，我们使用与之前实验相同的小鼠。将对从 B.1.351 恢复的小鼠进行行为测试，以检查 IL-1R1 的功能影响在本提案中，我们将共同探讨神经学基础的免疫机制。 COVID-19 期间功能障碍。