Mechanisms of age-related susceptibility to the chikungunya virus (CHIKV)
基孔肯雅病毒(CHIKV)与年龄相关的易感性机制
基本信息
- 批准号:10251001
- 负责人:
- 金额:$ 33.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-05-01 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAdultAfricanAgingAlphavirusAntibodiesAntibody FormationArthralgiaArthritisAsiansB-LymphocytesBrainCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCaribbean regionCellsCessation of lifeChikungunya virusChronicClinicalColorCountryDefectDiseaseElderlyEnvironmentEnvironmental Risk FactorEpidemicExanthemaExhibitsExposure toFeverFloridaGeneticHumanImmuneImmune System DiseasesImmune responseImmunityImpairmentIn Situ HybridizationIndividualInfectionInflammationInflammatoryInterferon-alphaInterleukin-17JointsKidneyKnockout MiceLeadLiverMeasuresMediatingModelingMorbidity - disease rateMusOrganOrganismOutcomePathogenesisPathogenicityPathologyPopulationPredispositionProductionRegulationReporterReportingRiskRisk FactorsRoleSerumSeverity of illnessSignal TransductionSurfaceT cell responseT-LymphocyteTestingTransforming Growth Factor betaViralViral PathogenesisVirusVirus DiseasesWild Type Mouseadaptive immune responseage relatedchikungunya infectioncytokineexperimental studyimmunological interventionimmunopathologyimprovedinsightjoint inflammationmacrophagemature animalmortalitymosquito-bornemouse modelneutralizing antibodypreventresponsetooltransmission processvector mosquitoviral resistanceyoung adult
项目摘要
Abstract
Chikungunya virus (CHIKV) is a reemerging alphavirus that recently spread throughout the world via its
mosquito vectors. The virus has high potential to inflict significant morbidity and mortality worldwide, including
the U.S., with initial transmissions reported in Florida. Older adults are particularly sensitive to severe CHIKV
disease (CHIKVD), which includes fever, rash, joint pain and sometimes involvement of parenchymal organs
(liver, brain, kidney). Moreover, CHIKVD tends to persist in many, particularly older, subjects in the form of
highly debilitating arthritis/arthralgia for months and years. While we are beginning to understand CHIKV
pathogenesis and immunity, we are far from even scratching the surface on the mechanisms of age-related
vulnerability to CHIKV.
We recently developed a mouse model which recapitulates age-related clinical outcomes observed in CHIKV-
infected elderly humans, and used it to begin to elucidate mechanisms underlying the age-related dysfunction
of the immune response to CHIKV infection. We found an increase in TGFβ, concomitant with qualitative and
quantitative impairments in B and T cell responses which failed to clear the virus. We showed that anti-TGFβ
antibody blockade could prevent the age-related increase in CHIKV disease severity, reduce joint pathology
and improve production of neutralizing antibodies. TGFβ was also elevated and neutralizing Ab reduced in
older humans suffering from CHIKV, making our model potentially directly relevant to older adults. Here, we
propose to dissect mechanisms that lead to dysregulated TGFβ production and to elucidate how TGFβ
contributes to increased pathology and decreased CHIKV control. Our central hypothesis is that that in old
CHIKV-infected mice, increased TGFβ dysregulates type 1 (T1) immunity against CHIKV by acting
upon soluble factors, Th1, B and perhaps Th17, cells. This hypothesis and related questions and sub-
hypotheses will be tested in the following Aims:
SA1. To test the roles of T and B cell-intrinsic and extrinsic (environmental) factors in suboptimal
adaptive responses of old mice to CHIKV.
SA2. To examine whether and how elevated TGFβ acts directly on old adaptive immune cells.
These experiments will provide detailed insights into pathogenesis and immunity against CHIKV and pave
the way for immune interventions against CHIKVD/chronic arthritis in older adults.
摘要
基孔肯雅病毒(CHIKV)是一种重新出现的甲病毒,最近通过其在世界各地传播。
蚊媒。该病毒很有可能在全世界造成严重的发病率和死亡率,包括
美国,最初的传播报告是在佛罗里达。老年人对严重的CHIKV特别敏感
疾病(CHIKVD),包括发热、皮疹、关节疼痛,有时累及实质器官
(肝、脑、肾)。此外,CHIKVD倾向于在许多受试者中,特别是老年受试者中,以CHIKVD的形式持续存在。
严重衰弱的关节炎/关节痛数月和数年。虽然我们开始了解CHIKV
发病机制和免疫,我们还远远没有触及表面上的机制与年龄有关
对CHIKV的脆弱性。
我们最近开发了一种小鼠模型,该模型概括了在CHIKV中观察到的年龄相关的临床结果。
感染老年人,并用它来开始阐明与年龄相关的功能障碍的潜在机制,
对CHIKV感染的免疫反应。我们发现TGFβ的增加,伴随着定性和
未能清除病毒的B和T细胞应答的定量损伤。我们发现抗TGF β
抗体阻断可以防止年龄相关的CHIKV疾病严重程度的增加,减少关节病理学,
并提高中和抗体的产生。TGFβ也升高,中和抗体降低,
患有CHIKV的老年人,使我们的模型可能与老年人直接相关。这里我们
我建议剖析导致TGFβ产生失调的机制,并阐明TGFβ
导致病理学增加和CHIKV控制降低。我们的核心假设是,在旧的
CHIKV感染的小鼠,通过作用增加TGFβ失调1型(T1)对CHIKV的免疫力
对可溶性因子Th 1、B和可能的Th 17细胞的影响。这个假设和相关的问题和子-
将在以下目标中检验假设:
SA 1.为了测试T和B细胞-内在和外在(环境)因素在次最佳治疗中的作用,
老年小鼠对CHIKV的适应性反应。
SA 2.研究升高的TGFβ是否以及如何直接作用于老年适应性免疫细胞。
这些实验将提供对CHIKV的发病机制和免疫的详细见解,并为CHIKV的免疫提供基础。
免疫干预对老年人CHIKVD/慢性关节炎的方式。
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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JANKO Z. NIKOLICH其他文献
JANKO Z. NIKOLICH的其他文献
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{{ truncateString('JANKO Z. NIKOLICH', 18)}}的其他基金
The role of CMV in HIV-associated accentuated aging
CMV 在 HIV 相关的加速衰老中的作用
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10760596 - 财政年份:2023
- 资助金额:
$ 33.77万 - 项目类别:
Mechanisms of age-related susceptibility to the chikungunya virus (CHIKV)
基孔肯雅病毒(CHIKV)与年龄相关的易感性机制
- 批准号:
10436970 - 财政年份:2018
- 资助金额:
$ 33.77万 - 项目类别:
Viral burden and systemic inflammation as biomarkers for chronic disease and frailty in aging
病毒负荷和全身炎症作为慢性疾病和衰老衰弱的生物标志物
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10153615 - 财政年份:2018
- 资助金额:
$ 33.77万 - 项目类别:
Viral burden and systemic inflammation as biomarkers for chronic disease and frailty in aging
病毒负荷和全身炎症作为慢性疾病和衰老衰弱的生物标志物
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10412933 - 财政年份:2018
- 资助金额:
$ 33.77万 - 项目类别:
Thymic and peripheral Aspects of T cell Aging and Rejuvenation
T 细胞衰老和再生的胸腺和外周方面
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Project 4: Thymic and peripheral Aspects of T cell Aging and Rejuvenation
项目 4:T 细胞衰老和再生的胸腺和外周方面
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10226925 - 财政年份:2017
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$ 33.77万 - 项目类别:
Peripheral T cell maintenance defects with aging
衰老导致外周 T 细胞维持缺陷
- 批准号:
10553995 - 财政年份:2017
- 资助金额:
$ 33.77万 - 项目类别:
Thymic and Peripheral Aspects of T Cell Aging and Rejuvenation
T 细胞衰老和再生的胸腺和外周方面
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10553988 - 财政年份:2017
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