IL-27 elicited antibodies: A novel means to control persistent Arenavirus infection
IL-27 引发抗体:控制持续性沙粒病毒感染的新方法
基本信息
- 批准号:9204389
- 负责人:
- 金额:$ 48.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-01-15 至 2020-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAfricaAnimal ModelAntibodiesAntiviral AgentsApplications GrantsArenaviridae InfectionsArenavirus InfectionsB-LymphocytesBiological Response ModifiersCD8-Positive T-LymphocytesCell physiologyConeDataDefectDevelopmentDiseaseDisease OutbreaksEbola virusEnvironmentEquilibriumFamilyFunctional disorderGenerationsHealth Care CostsHelper-Inducer T-LymphocyteHumanIgG1ImmuneImmune responseImmunoglobulin GImmunosuppressive AgentsInfectionInfection ControlInterleukin-10Interleukin-6LifeLightLymphocytic choriomeningitis virusModelingMusNatureOutcomePlasmaPlayProductionPropertyPublic HealthRoleSignal TransductionStudy modelsT cell responseT-LymphocyteTimeTranslatingVaccine DesignViralViral AntibodiesVirusVirus Diseasesadaptive immune responseantiviral immunitybasecombatcytokineexhaustionin vivomemberneglectnovelpublic health relevancepurgeresponsetherapy design
项目摘要
DESCRIPTION (provided by applicant): Persistent virus infections cause disease in hundreds of millions of people and exert constant strain on the global economy due to healthcare costs. While progress has been made towards understanding mechanisms that allow viruses to persist, therapies to control persistent viruses are not optimal due an incomplete understanding of the factors involved in virus persistence. One common theme that accompanies virus persistence is an exhaustive or hypo-responsive state of adaptive immune response. This phenomenon was first described using the staple animal model for studying virus persistence, Lymphocytic Choriomeningitis Virus (LCMV), in its natural mouse host and extended to human persistent infections. Using this model, it was revealed that a balance between positive and negative immune regulatory molecules is essential to purge virus infection. One of the most extensively studied mechanisms contributing to virus persistence has been T cell exhaustion, which is potentiated by negative immune regulatory molecules such as IL-10 and PD-1. Interestingly, the absence of two positive immune regulatory molecules, IL-6 and IL-21, result in the inability to control persistent virus infection. These molecules are known to be important for B cell function. However, studies on whether B cells also control persistent virus infection have been neglected and their role remains unknown. A newly discovered member of the IL-6 family, IL-27, modulates both B and T cell responses during infection. However, few studies have examined how IL-27 affects antiviral immune responses. I began studying how IL-27 deletion affects the outcome of both acute and persistent LCMV infection. I made the observation that IL-27-deficiency resulted in prolonged LCMV clone-13 persistence. Prolonged virus persistence in IL-27-/- mice correlated with defects in both T and B cell responses. Virus specific T cells in IL-
27-/- mice displayed exacerbated T cell exhaustion following clone-13 infection. Moreover, I discovered that IL- 27-/- mice made elevated levels of IgG1 with minimal production of IgG2a, compared to predominant production of IgG2a in IL-27+/+ hosts. I further demonstrated that development of plasma B cells (the major antibody producers) and anti-LCMV IgG production is required to control clone-13 infection, indicating that antibody likely plays an important role in controlling persistent virus infection. This grant proposal aims to elucidate the mechanisms by which IL-27-deficiency leads to prolonged LCMV persistence. The aims are focused on understanding how IL-27 contributes to altered antiviral T and B cell responses and whether IL-27 signaling on T or B cells is essential to purge persistent LCMV infection. The absence of IgG2a production during persistent virus infection in IL-27-deficient mice suggests that IL-27- dependent induction of IgG2a may be essential to control persistent virus infection. The possibility that a specific antibody isotype may be essential to purge persistent virus infection i novel and will be investigated within this proposal.
描述(由申请人提供):持续的病毒感染导致数亿人患病,并由于医疗费用而给全球经济带来持续的压力。虽然在理解病毒持续存在的机制方面已经取得了进展,但由于对病毒持续存在所涉及的因素的了解不完全,控制持续性病毒的疗法并不是最佳的。伴随病毒持续存在的一个常见主题是适应性免疫反应的穷尽或低反应状态。这种现象首先是使用研究病毒持久性的主要动物模型——淋巴细胞脉络膜脑膜炎病毒(LCMV)在其天然小鼠宿主中描述的,并扩展到人类持续性感染。使用该模型,研究表明,阳性和阴性免疫调节分子之间的平衡对于清除病毒感染至关重要。 T 细胞耗竭是导致病毒持久性的最广泛研究的机制之一,IL-10 和 PD-1 等负性免疫调节分子会增强 T 细胞耗竭。有趣的是,缺乏两种阳性免疫调节分子IL-6和IL-21,导致无法控制持续的病毒感染。已知这些分子对 B 细胞功能很重要。然而,关于 B 细胞是否也控制持续病毒感染的研究却被忽视,其作用仍然未知。 IL-27 是 IL-6 家族新发现的成员,可在感染过程中调节 B 细胞和 T 细胞反应。然而,很少有研究探讨 IL-27 如何影响抗病毒免疫反应。我开始研究 IL-27 缺失如何影响急性和持续性 LCMV 感染的结果。我观察到 IL-27 缺乏会导致 LCMV 克隆 13 的持久性延长。 IL-27-/- 小鼠中病毒持续存在时间延长与 T 细胞和 B 细胞反应缺陷相关。 IL- 中的病毒特异性 T 细胞
27-/- 小鼠在克隆 13 感染后表现出 T 细胞耗竭加剧。此外,我发现与 IL-27+/+ 宿主中 IgG2a 的主要产生相比,IL-27-/- 小鼠的 IgG1 水平升高,而 IgG2a 的产生最少。我进一步证明,控制克隆 13 感染需要血浆 B 细胞(主要抗体产生者)的发育和抗 LCMV IgG 的产生,这表明抗体可能在控制持续性病毒感染中发挥重要作用。该拨款提案旨在阐明 IL-27 缺乏导致 LCMV 持久性延长的机制。目的是了解 IL-27 如何影响 T 细胞和 B 细胞的抗病毒反应,以及 T 细胞或 B 细胞上的 IL-27 信号传导是否对于清除持续性 LCMV 感染至关重要。 IL-27缺陷型小鼠在持续性病毒感染期间不产生IgG2a,这表明IL-27依赖性的IgG2a诱导可能对于控制持续性病毒感染至关重要。特定抗体同种型对于清除持续性病毒感染可能至关重要,这一可能性是新颖的,并将在本提案中进行研究。
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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John Ross Teijaro其他文献
John Ross Teijaro的其他文献
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{{ truncateString('John Ross Teijaro', 18)}}的其他基金
The role of IL-27 in sustaining the exhausted CD8 T cell response to persistent infection and cancer.
IL-27 在维持耗尽的 CD8 T 细胞对持续感染和癌症的反应中的作用。
- 批准号:
10445313 - 财政年份:2021
- 资助金额:
$ 48.13万 - 项目类别:
The role of IL-27 in sustaining the exhausted CD8 T cell response to persistent infection and cancer.
IL-27 在维持耗尽的 CD8 T 细胞对持续感染和癌症的反应中的作用。
- 批准号:
10316578 - 财政年份:2021
- 资助金额:
$ 48.13万 - 项目类别:
The role of IL-27 in sustaining the exhausted CD8 T cell response to persistent infection and cancer.
IL-27 在维持耗尽的 CD8 T 细胞对持续感染和癌症的反应中的作用。
- 批准号:
10650747 - 财政年份:2021
- 资助金额:
$ 48.13万 - 项目类别:
Engineer Immune Cells via Chemoenzymatic Glycan Editing
通过化学酶聚糖编辑工程免疫细胞
- 批准号:
10350593 - 财政年份:2019
- 资助金额:
$ 48.13万 - 项目类别:
Engineer Immune Cells via Chemoenzymatic Glycan Editing
通过化学酶聚糖编辑工程免疫细胞
- 批准号:
10578671 - 财政年份:2019
- 资助金额:
$ 48.13万 - 项目类别:
Novel Strategies for Controlling Persistent Viral Infection
控制持续病毒感染的新策略
- 批准号:
9077410 - 财政年份:2016
- 资助金额:
$ 48.13万 - 项目类别:
Novel Strategies for Controlling Persistent Viral Infection
控制持续病毒感染的新策略
- 批准号:
9248857 - 财政年份:2016
- 资助金额:
$ 48.13万 - 项目类别:
The Role of IL-27 in Controlling Persistent Viral Infection
IL-27 在控制持续病毒感染中的作用
- 批准号:
8897666 - 财政年份:2014
- 资助金额:
$ 48.13万 - 项目类别:
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