NK cell mobilization as a pathogenic etiology of SARS-CoV-2 gastrointestinal disease
NK 细胞动员作为 SARS-CoV-2 胃肠道疾病的致病病因
基本信息
- 批准号:10626025
- 负责人:
- 金额:$ 40.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVActivated Natural Killer CellAffectAntibodiesAntibody ResponseAntibody-Dependent EnhancementAntigensAntiviral ResponseBindingCOVID-19COVID-19 patientCOVID-19 preventionCOVID-19 treatmentCOVID-19 vaccineCellsContainmentCoronavirus InfectionsCytomegalovirusDigestive System DisordersDisease OutbreaksDisease OutcomeEffector CellEndowmentEpitheliumEpitopesEtiologyExhibitsExposure toFutureGastrointestinal DiseasesGastrointestinal tract structureGut MucosaHIVHomingHumanImmuneImmune System DiseasesImmune responseImmunotherapeutic agentIndividualInfectionInflammationInflammatoryInflammatory ResponseInfluenzaInjuryInnate Immune SystemK562 CellsKnowledgeLeftMacacaMediatingMemoryModelingMucous MembraneNatural Killer CellsNucleocapsidPathogenesisPathogenicityPathologyPeptidesPersonsPhenotypePhysiologic pulsePlayPreventionPrimatesPropertyPublic HealthReportingRespiratory DiseaseRespiratory Tract InfectionsRoleSARS-CoV-2 infectionSARS-CoV-2 pathogenesisSIVSeverity of illnessSurfaceSymptomsT-LymphocyteTestingTherapeutic InterventionTissuesVaccinesViralViral PhysiologyVirusVirus DiseasesVirus ReplicationWorkcytotoxicitydata submissionexperimental studyimmune functionimmunopathologyinfluenza infectioninnovationlung injurymouse modelnonhuman primatenovelpandemic diseasereceptorrecruitresponsesensitizing antigensevere COVID-19trafficking
项目摘要
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of Coronavirus
Disease 2019 (COVID-19) and its rapid global spread has led to an unprecedented global public health crisis.
Currently, treatment options are very limited and vaccines against SARS-CoV-2 are still pending widespread
use. Host immune responses to SARS-CoV-2 play a crucial role in the containment of the infection. Although
SARS-CoV-2 is generally thought of as a respiratory disease, an unexpected consequence is severe
complications of the gastrointestinal tract (GIT). Indeed, up to two-thirds of COVID-19 patients have some GIT
symptoms and several lines of evidence suggest a breakdown of the epithelial barrier resulting in widespread
inflammation.
While recent studies in COVID-19 patients and nonhuman primate (NHP) models described T lymphocytes
and antibody responses, less is known about natural killer (NK) cell responses in SARS-CoV-2 infection.
Classically, NK cells are viewed as nonspecific effector cells of the innate immune system that play critical roles
in defense against viral infections. However, besides their ability to rapidly eliminate virus-infected cells without
the need for prior antigen sensitization, NK cells also exhibit adaptive immune functions. Different forms of
adaptive capabilities have been identified among human NK cell subpopulations, including reports of true
antigen-specific memory NK cells as well as adaptive NK cells with enhanced antibody-dependent functions. NK
cells may be crucial for early containment of SARS-CoV-2 and formation of adaptive responses elicited by
infection, yet uncontrolled NK response may also contribute to the hyperinflammatory responses observed in
COVID-19 patients, including in the GIT. In this proposal we will use NHP models, which recapitulate viral
replication, immune responses and disease pathology observed in human COVID-19 infection, to test the
following hypotheses: (i) pathogenic inflammation in the gastrointestinal tract in COVID-19 is a
consequence, in part, of dysregulated or exacerbated NK cell responses, and (ii) specific subsets of NK
cells mediate potent anti-viral responses against SARS-CoV-2, associated with enhanced viral clearance
and reduced disease severity. We will address these hypotheses through two specific aims: 1. Determine the
contribution of systemic and GIT NK cell mobilization to SARS-CoV-2 pathogenesis and clearance in macaque
models; 2. Evaluate the mechanisms by which specific innate and adaptive NK cell subpopulations modulate
SARS-CoV-2 infection in the GIT. If successful, the results of these innovative studies will contribute new
knowledge of human immune responses against SARS-CoV-2 and provide the rationale to develop novel
immunotherapeutic approaches to target specific NK cell subsets that could substantially contribute to prevent
and treat COVID-19.
严重急性呼吸综合征冠状病毒2型是冠状病毒的病原体。
疾病2019(新冠肺炎)及其在全球的快速传播导致了一场前所未有的全球公共卫生危机。
目前,治疗选择非常有限,针对SARS-CoV-2的疫苗仍有待广泛应用
使用。宿主对SARS-CoV-2的免疫应答在控制感染中起着至关重要的作用。虽然
SARS-CoV-2通常被认为是一种呼吸系统疾病,意外的后果是严重的
胃肠道并发症(GIT)。事实上,多达三分之二的新冠肺炎患者有一些痛楚
症状和几条证据表明上皮屏障的破坏导致广泛的
发炎。
而最近在新冠肺炎患者和非人灵长类动物模型中的研究描述了T淋巴细胞
和抗体反应,对SARS-CoV-2感染中的自然杀伤(NK)细胞反应知之甚少。
传统上,NK细胞被视为先天免疫系统的非特异性效应细胞,发挥着关键作用。
用来防御病毒感染。然而,除了能够在没有病毒的情况下快速消除病毒感染的细胞外,
由于需要事先的抗原致敏,NK细胞也表现出适应性免疫功能。不同形式的
已经在人类NK细胞亚群中发现了适应能力,包括真的
抗原特异性记忆NK细胞以及具有增强抗体依赖功能的适应性NK细胞。NK
细胞可能对SARS-CoV-2的早期遏制和由以下因素引发的适应性反应的形成至关重要
感染,但不受控制的NK反应也可能导致观察到的高炎症反应
新冠肺炎患者,包括在胃肠道。在本提案中,我们将使用NHP模型,该模型概括了病毒
在新冠肺炎感染中观察到的复制、免疫反应和疾病病理,以测试
以下假设:(I)新冠肺炎胃肠道的致病性炎症是一种
部分原因是NK细胞反应失调或加剧,以及(2)NK细胞的特定亚群
细胞介导针对SARS-CoV-2的强大抗病毒反应,与增强病毒清除有关
并降低了疾病的严重性。我们将通过两个具体目标来解决这些假设:1.确定
全身和GIT NK细胞动员在SARS-CoV-2致病和猕猴清除中的作用
模型;2.评估特定的先天和适应性NK细胞亚群调节机制
胃肠道感染SARS-CoV-2。如果成功,这些创新研究的结果将做出新的贡献
了解人类对SARS-CoV-2的免疫反应,并为开发新型病毒提供理论基础
针对特定NK细胞亚群的免疫治疗方法,可显著有助于预防
请你吃新冠肺炎。
项目成果
期刊论文数量(0)
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Roger Keith Reeves其他文献
Roger Keith Reeves的其他文献
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{{ truncateString('Roger Keith Reeves', 18)}}的其他基金
Microbial and innate immune mechanisms of oral inflammation during SIV infection
SIV感染期间口腔炎症的微生物和先天免疫机制
- 批准号:
10408915 - 财政年份:2021
- 资助金额:
$ 40.25万 - 项目类别:
NK cell mobilization as a pathogenic etiology of SARS-CoV-2 gastrointestinal disease
NK 细胞动员作为 SARS-CoV-2 胃肠道疾病的致病病因
- 批准号:
10319735 - 财政年份:2021
- 资助金额:
$ 40.25万 - 项目类别:
Mechanisms of Natural Killer Cell Clearance of SIV from Lymphoid Follicles
淋巴滤泡自然杀伤细胞清除 SIV 的机制
- 批准号:
10408913 - 财政年份:2021
- 资助金额:
$ 40.25万 - 项目类别:
NK cell mobilization as a pathogenic etiology of SARS-CoV-2 gastrointestinal disease
NK 细胞动员作为 SARS-CoV-2 胃肠道疾病的致病病因
- 批准号:
10458737 - 财政年份:2021
- 资助金额:
$ 40.25万 - 项目类别:
Mechanisms of Natural Killer Cell Clearance of SIV from Lymphoid Follicles
淋巴滤泡自然杀伤细胞清除 SIV 的机制
- 批准号:
10305659 - 财政年份:2021
- 资助金额:
$ 40.25万 - 项目类别:
Mechanisms of Natural Killer Cell Clearance of SIV from Lymphoid Follicles
淋巴滤泡自然杀伤细胞清除 SIV 的机制
- 批准号:
10529270 - 财政年份:2021
- 资助金额:
$ 40.25万 - 项目类别:
Antigen-Specific NK Cell Memory Against SIV and HIV Vaccines
针对 SIV 和 HIV 疫苗的抗原特异性 NK 细胞记忆
- 批准号:
10408910 - 财政年份:2021
- 资助金额:
$ 40.25万 - 项目类别:
Natural killer cell receptor-expressing B cells as regulators of mucosal immunity in SIV infection
表达自然杀伤细胞受体的 B 细胞作为 SIV 感染粘膜免疫的调节剂
- 批准号:
10451069 - 财政年份:2021
- 资助金额:
$ 40.25万 - 项目类别:
Natural killer cell receptor-expressing B cells as regulators of mucosal immunity in SIV infection
表达自然杀伤细胞受体的 B 细胞作为 SIV 感染粘膜免疫的调节剂
- 批准号:
9927204 - 财政年份:2019
- 资助金额:
$ 40.25万 - 项目类别:
Antigen-Specific NK Cell Memory Against SIV and HIV Vaccines
针对 SIV 和 HIV 疫苗的抗原特异性 NK 细胞记忆
- 批准号:
9405715 - 财政年份:2017
- 资助金额:
$ 40.25万 - 项目类别: