Innate immune mechanisms of virologic control and recovery from flavivirus encephalitis
黄病毒脑炎病毒学控制和恢复的先天免疫机制
基本信息
- 批准号:10247164
- 负责人:
- 金额:$ 77.53万
- 依托单位:
- 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:2020-09-14 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdaptor Signaling ProteinAddressAlphavirusAntigensAntiviral AgentsArbovirusesAstrocytesBrainBunyaviridaeCD8-Positive T-LymphocytesCellsCentral Nervous System Viral DiseasesChemotactic FactorsCognitive deficitsComplementComplement 1qConsequentialismDefectDevelopmentDiagnosisEncephalitisEpidemicEquilibriumFlavivirusGene ExpressionGene Expression ProfilingHematopoieticHippocampus (Brain)HomeostasisHumanImmuneImmune responseImmune systemImmunologicsImpaired cognitionInfectionInflammationInflammatoryInnate Immune ResponseInterferon Type IIInterferonsInterleukin-1LeadLearningMediatingMemoryMicrogliaMitochondriaMitochondrial ProteinsMosquito-Borne EncephalitisMusNatureNeurocognitiveNeurologicNeuronal InjuryNeuronsPathogenesisPathologyPhaseProcessProductionProteinsRNA HelicaseRecoverySignal TransductionSignaling ProteinSkinSocial InteractionSpecificitySpleenSurvivorsSynapsesT cell responseT memory cellT-LymphocyteTNF geneTherapeuticTimeTissuesVaccine DesignViralViral EncephalitisVirusVirus DiseasesVirus ReplicationWest Nile viral infectionWest Nile virusbasechemokinecytokineimmunoregulationinnate immune mechanismslymph nodesmosquito-bornemouse modelneural correlateneurogenesisneurotropicneurotropic viruspresynapticprogramsrecruitrelating to nervous systemrepairedresponsesynaptogenesistick-bornevirology
项目摘要
ABSTRACT
Viral infections within the brain pose a unique challenge for the immune system: the host must trigger an effective
immune response to control and clear the infection while minimizing neuronal damage. The immunological
mechanisms that balance these responses during neurotropic virus infection are not well understood. West Nile
virus (WNV) is an emerging neurotropic flavivirus that causes annual epidemics of mosquito-borne encephalitis
on a global scale. Following delivery into the skin, WNV replicates in the lymph nodes and spleen followed by
entry into the CNS. Here, WNV infects and replicates within neurons, where it is detected by the cytoplasmic
RNA helicases RIG-I and MDA5 which, via activation of the mitochondrial antiviral signaling protein (MAVS),
lead to the expression of antiviral and proinflammatory proteins, including T cell chemoattractants. The absence
of CD8+ T cells leads to uncontrolled virus replication, significant neuronal injury within the brain and loss of
protection. To understand how the brain impacts T cell responses during WNV infection, we performed
transcriptional profiling on antigen-specific CD8+ T cells isolated from the spleen and brain at early and late
times post-WNV infection. We observed that antigen-specific CD8+ T cells infiltrate the CNS around day 7 post-
infection (pi), were polyfunctional (IFN-γ, TNF-α) and persist in the brain through day 90 pi. Subpopulations of
persistent CD8+ T cells were observed to develop markers consistent with resident memory T cells and maintain
persistently elevated levels of type II IFN (IFN-γ). We recently found that CD8+ T cell-derived IFN-γ signaling
to microglia, in conjunction with the expression of complement, drives the elimination of presynaptic termini
within the hippocampus, which underlies spatial learning defects during recovery from WNV. Further, IFN-γ
signaling also promotes astrocyte expression of interleukin (IL)-1, which limits synaptic repair. These findings
strongly suggest that the brain microenvironment impacts CD8+ T cell programming that is important for
mediating viral control during the acute phase of infection. However, these same antigen-specific CD8+ T cells,
through the actions of IFN-γ, contribute to cognitive deficits during the recovery phase. Based on these
observations, we hypothesize that during the acute phase of WNV infection, MAVS signaling within neurons and
are important for coordinating CD8+ T cell-mediated viral control, neural synapse formation and neurogenesis.
However, during the recovery phase, we believe that MAVS signaling within neurons and microglia promote
persistence of brain- resident antigen-specific CD8+ T cells that contribute to defects in spatial learning. To
address these hypotheses, we seek to determine: 1) the cell-specific contribution of MAVS signaling within the
brain during acute WNV infection; and 2) the impact of CD8+ T cell persistence on CNS homeostasis after
recovery from viral encephalitis. This study will reveal the cell-specific regulatory processes that promote
antigen-specific CD8+ T cell-mediated viral control while minimizing neurologic sequelae within the brain
following recovery from infection.
摘要
大脑内的病毒感染对免疫系统构成了独特的挑战:宿主必须触发有效的免疫系统,
免疫反应,以控制和清除感染,同时最大限度地减少神经元损伤。免疫
在嗜神经病毒感染期间平衡这些反应的机制还没有很好的理解。西尼罗河
西尼罗河病毒是一种新出现的嗜神经黄病毒,每年引起蚊媒脑炎流行
在全球范围内。在递送到皮肤中后,WNV在淋巴结和脾中复制,随后在淋巴结和脾中复制。
进入CNS。在这里,西尼罗河病毒感染和复制的神经元内,它是由细胞质检测
RNA解旋酶RIG-I和MDA 5,通过激活线粒体抗病毒信号蛋白(MAVS),
导致抗病毒和促炎蛋白的表达,包括T细胞化学引诱物。没有
CD 8 + T细胞的过度增殖导致病毒复制失控,脑内严重的神经元损伤和免疫功能丧失。
保护为了了解大脑在WNV感染期间如何影响T细胞反应,我们进行了
从早期和晚期的脾和脑中分离的抗原特异性CD 8 + T细胞的转录谱分析
感染西尼罗河病毒后10次。我们观察到,抗原特异性CD 8 + T细胞浸润中枢神经系统后7天左右,
感染(pi)后,是多功能的(IFN-γ,TNF-α),并持续存在于脑中直至pi第90天。亚群
观察到持续的CD 8 + T细胞产生与常驻记忆T细胞一致的标记物,并维持
持续升高的II型IFN(IFN-γ)水平。我们最近发现,CD 8 + T细胞来源的IFN-γ信号转导
结合补体的表达,驱动突触前末端的消除,
海马内,这是从西尼罗河恢复期间空间学习缺陷的基础。此外,IFN-γ
信号传导还促进星形胶质细胞表达白细胞介素(IL)-1,这限制了突触修复。这些发现
这强烈表明,大脑微环境影响CD 8 + T细胞编程,这对于
在感染的急性期介导病毒控制。然而,这些抗原特异性CD 8 + T细胞,
通过IFN-γ的作用,在恢复阶段导致认知缺陷。基于这些
观察,我们假设在WNV感染的急性期,神经元内的MAVS信号传导,
对于协调CD 8 + T细胞介导的病毒控制、神经突触形成和神经发生是重要的。
然而,在恢复阶段,我们认为神经元和小胶质细胞内的MAVS信号促进了神经元和小胶质细胞的凋亡。
脑驻留抗原特异性CD 8 + T细胞的持续存在导致空间学习的缺陷。到
为了解决这些假设,我们试图确定:1)MAVS信号传导在细胞内的细胞特异性贡献,
急性西尼罗河病毒感染期间的脑;和2)CD 8 + T细胞持久性对急性西尼罗河病毒感染后CNS稳态的影响。
从病毒性脑炎中恢复过来这项研究将揭示细胞特异性的调节过程,
抗原特异性CD 8 + T细胞介导的病毒控制,同时最大限度地减少脑内神经系统后遗症
从感染中恢复过来。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Robyn S Klein其他文献
West Nile virus: crossing the blood-brain barrier
西尼罗河病毒:穿越血脑屏障
- DOI:
10.1038/nm1204-1294 - 发表时间:
2004-12-01 - 期刊:
- 影响因子:50.000
- 作者:
Michael S Diamond;Robyn S Klein - 通讯作者:
Robyn S Klein
Infectious diseases research in 2024: insights into dementia
2024 年传染病研究:对痴呆症的见解
- DOI:
10.1016/s1474-4422(24)00497-6 - 发表时间:
2025-01-01 - 期刊:
- 影响因子:45.500
- 作者:
Robyn S Klein - 通讯作者:
Robyn S Klein
Robyn S Klein的其他文献
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{{ truncateString('Robyn S Klein', 18)}}的其他基金
2023 Neuroimmune Communication in Health and Disease Gordon Research Conference and Gordon Research Seminar
2023健康与疾病中的神经免疫通讯戈登研究会议暨戈登研究研讨会
- 批准号:
10609280 - 财政年份:2022
- 资助金额:
$ 77.53万 - 项目类别:
Research Program Award (R35 Clinical Trial Optional) - Dr. Robyn Klein NINDS
研究计划奖(R35 临床试验可选)- Robyn Klein NINDS 博士
- 批准号:
10397683 - 财政年份:2021
- 资助金额:
$ 77.53万 - 项目类别:
Research Program Award (R35 Clinical Trial Optional) - Dr. Robyn Klein NINDS
研究计划奖(R35 临床试验可选)- Robyn Klein NINDS 博士
- 批准号:
10239672 - 财政年份:2021
- 资助金额:
$ 77.53万 - 项目类别:
Astrocyte innate immune mechanisms of post-viral cognitive dysfunction
病毒后认知功能障碍的星形胶质细胞先天免疫机制
- 批准号:
10115451 - 财政年份:2020
- 资助金额:
$ 77.53万 - 项目类别:
Mechanisms of sex differences in blood-brain barrier biology
血脑屏障生物学中性别差异的机制
- 批准号:
9090530 - 财政年份:2016
- 资助金额:
$ 77.53万 - 项目类别:
Mechanisms of sex differences in blood-brain barrier biology
血脑屏障生物学中性别差异的机制
- 批准号:
9204440 - 财政年份:2016
- 资助金额:
$ 77.53万 - 项目类别:
Targeting the BBB to treat CNS inflammation
靶向 BBB 治疗中枢神经系统炎症
- 批准号:
8826187 - 财政年份:2008
- 资助金额:
$ 77.53万 - 项目类别:
Targeting the BBB to treat CNS inflammation
靶向 BBB 治疗中枢神经系统炎症
- 批准号:
9275040 - 财政年份:2008
- 资助金额:
$ 77.53万 - 项目类别:
Targeting the BBB to treat CNS inflammation
靶向 BBB 治疗中枢神经系统炎症
- 批准号:
8741885 - 财政年份:2008
- 资助金额:
$ 77.53万 - 项目类别: