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
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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: