Cytokine-mediated neurologic disease in COVID-19

COVID-19 中细胞因子介导的神经系统疾病

• 批准号: 10509125
• 负责人: Abigail Rose Vanderheiden
• 金额: $ 6.99万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10509125
• 关键词: 2019-nCoV; Acute; Address; Anosmia; Anxiety; Astrocytes; Attention; Attentional deficit; Autopsy; Behavior Control; Behavioral; Blood - brain barrier anatomy; Body Weight decreased; Brain; Brain region; C57BL/6 Mouse; Cells; Cognition; Cognitive deficits; Communicable Diseases; Coronavirus; Coughing; Cre-LoxP; Data; Defect; Endothelial Cells; Fatigue; Fever; Follow-Up Studies; Functional disorder; Generations; Hamsters; Headache; Hemorrhage; Hippocampus (Brain); Human; Hypoxia; Immune; Immune response; Immune signaling; Immunohistochemistry; Immunologics; Impaired cognition; In Vitro; Individual; Infarction; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Interleukin-1 beta; Interleukin-9; Interleukins; Ischemia; Learning; LoxP-flanked allele; Lung; Mediating; Memory; Memory impairment; Microglia; Modeling; Movement Disorders; Mus; Nervous System Trauma; Neuraxis; Neurologic Dysfunctions; Neurologic Symptoms; Neurons; Nodule; Pathogenesis; Patients; Peripheral; Pharmacological Treatment; Play; Process; Production; Psychoses; Recovery; Reporting; Resolution; Respiratory Disease; Respiratory System; Role; SARS-CoV-2 B.1.351; SARS-CoV-2 infection; Sampling; 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; immune activation; insight; mouse model; nerve stem cell; nervous system disorder; neural correlate; neurogenesis; neuroimaging; neuroinflammation; neurotoxic; novel; pandemic disease; post SARS-CoV-2 infection; receptor; recruit; response; spatial memory; stem cell differentiation; synaptogenesis

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.

项目摘要 新出现的冠状病毒SARS-COV-2引起了历史悠久的呼吸道疾病大流行（covid- 19）。一个令人惊讶的发现是，轻度和重度Covid-19都与持续的神经系统有关 症状，即使在感染解决后也是如此。患者出现多种症状，定义 注意，计划和其他执行功能，记忆力障碍或新的精神病。验尸 对COVID-19的个体的大脑进行分析，没有找到传染性SARS-COV-2的证据 实质。然而，COVID-19感染与一系列神经损伤有关，包括Infacts， 缺血，出血和缺氧。验尸标本的免疫组织化学表明 SARS-COV-2感染与血脑屏障（BBB）中断有关 炎性细胞因子，IL-1β，小胶质细胞激活和结节，以及神经噬菌体。在其他神经病毒中 病毒感染，IL-1β通过破坏血脑会促进中枢神经系统的感染 激活小胶质细胞的免疫细胞的障碍和募集，从而消除了海马中的突触 大脑区域对于学习和记忆至关重要。在恢复过程中，IL-1β抑制神经发生，这限制了突触 恢复并引起空间记忆缺陷。我们假设在SARS- COV-2感染电位通过破坏BBB并促进认知和记忆来神经功能障碍 缺陷。为了调查这一点，我们将使用COVID-19的C57BL/6小鼠模型，其中小鼠是鼻内的 被B.1.351（Beta变体）感染，自然会感染小鼠。在AIM 1中，我们将研究IL-1R1的作用 使用脑微血管内皮细胞（BMEC）特定诱导CRE交叉的BBB破坏信号传导 到IL-1R的小鼠。我们还将确定IL-1R1信号是否促进了BMEC的激活和诱导 炎症。在AIM 2中，我们将探讨IL-1R1信号传导是否通过抑制会影响认知和记忆 正在进行的突触消除中的神经发生。首先，我们将确定IL-1R1对神经发生的影响 在使用B.1.351感染期间，使用神经干细胞（NSC）特异性，可诱导的CRE小鼠越过IL-1R 老鼠。接下来，我们测试IL-1R1信号传导对通过NSC-恢复海马三突触cirucuit的作用 特异性或小胶质特异性CRE-IL-1R1 Floxed小鼠。最后，使用与以前的实验相同的小鼠，我们 将对从B.1.351回收的小鼠进行行为测试，以检查IL-1R1的功能影响 信号。在这一建议中，我们将探讨神经系统基础的免疫学机制 COVID-19期间的功能障碍。