Cytokine-mediated neurologic disease in COVID-19
Cytokine-mediated neurologic disease in COVID-19
批准号:
10704594
负责人:
Abigail Rose Vanderheiden
金额:
$7.22万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-09-01 至 2024-08-31
关键词:
2019-nCoVAcuteAddressAnosmiaAnxietyAstrocytesAttentionAttentional deficitAutopsyBehavior ControlBehavioralBlood - brain barrier anatomyBlood brain barrier dysfunctionBody Weight decreasedBrainBrain regionC57BL/6 MouseCOVID-19COVID-19 pathogenesisCOVID-19 patientCellsCentral Nervous SystemCognitionCognitive deficitsCommunicable DiseasesCoronavirusCoughingCre-LoxPDataDefectEndothelial CellsFatigueFeverFollow-Up StudiesGenerationsHamstersHeadacheHemorrhageHippocampusHumanHypoxiaIL1R1 geneImmuneImmune responseImmune signalingImmunohistochemistryImmunologicsImpaired cognitionIn VitroIndividualInfarctionInfectionInflammationInflammatoryInflammatory ResponseInjuryInterleukin-1Interleukin-1 betaIschemiaLearningLoxP-flanked alleleLungMediatingMemoryMemory impairmentMicrogliaModelingMovement DisordersMusNervous System TraumaNeuroimmunomodulationNeurologic DysfunctionsNeurologic SymptomsNeuronsNodulePatientsPeripheralPharmacological TreatmentProductionPsychosesRecoveryReportingResolutionRespiratory DiseaseRespiratory SystemRoleSARS-CoV-2 B.1.351SARS-CoV-2 infectionSamplingSignal InductionSignal PathwaySignal TransductionSourceSpecimenSurveysSymptomsSynapsesSyndromeTestingTight JunctionsTissuesVariantViral Load resultVirus Diseasesabstractingattentional controlaxon injurybehavior testbetacoronavirusblood-brain barrier disruptionblood-brain barrier permeabilizationbrain endothelial cellcytokineexcitatory neuronexecutive functionexperimental studyglial activationimmune activationinducible Creinsightmouse modelnerve stem cellnervous system disorderneural correlateneurogenesisneuroimagingneuroinflammationneurotoxicnovelnovel coronaviruspandemic diseasepost SARS-CoV-2 infectionreceptorrecruitresponsesevere COVID-19spatial memorystem cell differentiationsynaptogenesis
中文摘要
项目摘要
新出现的冠状病毒,SARS-CoV-2,已经引起了历史性的呼吸道疾病大流行(COVID-19)。
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疾病有关。
症状,甚至在感染消退后。患者表现出各种症状,
注意力,计划和其他执行功能,记忆障碍,或新的精神病。验尸
对COVID-19患者大脑的分析没有发现感染SARS-CoV-2的证据,
薄壁组织然而,COVID-19感染与一系列神经损伤有关,包括梗死,
缺血、血管扩张和缺氧。尸检标本的免疫组织化学显示,
SARS-CoV-2感染与血脑屏障(BBB)破坏、血脑屏障前体蛋白水平升高有关。
炎性细胞因子、IL-1β和小胶质细胞活化和结节以及神经元吞噬。在其他神经毒性
病毒感染时,IL-1β通过破坏血脑,促进中枢神经系统炎症
屏障和招募免疫细胞激活小胶质细胞,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抑制神经发生,从而限制突触
恢复,并诱导空间记忆缺陷。我们假设SARS期间脑中IL-1β的产生-
CoV-2感染通过破坏BBB并促进认知和记忆来增强神经功能障碍
赤字为了研究这一点,我们将使用COVID-19的C57 Bl/6小鼠模型,其中小鼠鼻内注射
感染了B.1.351(β变体),其自然感染小鼠。在目的1中,我们将研究IL-1 R1在
使用脑微血管内皮细胞(BMEC)特异性可诱导Cre交叉的BBB破坏的信号传导
IL-1 R floxed小鼠。我们还将确定IL-1 R1信号传导是否促进BMEC的激活和诱导BMEC的表达。
炎症。在目标2中,我们将探索IL-1 R1信号传导是否通过抑制
突触消除过程中的神经发生首先,我们将确定IL-1 R1对神经发生的影响。
在用B.1.351感染期间,使用神经干细胞(NSC)特异性的、与IL-1 R floxed杂交的可诱导Cre小鼠
小鼠接下来,我们通过NSC检测IL-1 R1信号在海马三突触回路恢复中的作用。
特异性或小胶质细胞特异性Cre-IL-1 R1 floxed小鼠。最后,使用与之前实验相同的小鼠,我们
将对从B.1.351中恢复的小鼠进行行为测试,以检查IL-1 R1的功能影响
发信号。在这个提议中,我们将共同探索神经系统疾病的免疫机制,
在COVID-19期间出现功能障碍。
英文摘要
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.
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会议论文
Cytokine-mediated neurologic disease in COVID-19
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批准号:10509125
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项目类别:
-
资助金额:$6.99万
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财政年份:2022
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负责人:Abigail Rose Vanderheiden
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依托单位:
海外基金