Genetic Susceptibility of Antibody-dependent Enhancement of Flaviviruses
黄病毒抗体依赖性增强的遗传易感性
基本信息
- 批准号:9815044
- 负责人:
- 金额:$ 25.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-05 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAllelesAmino AcidsAntibodiesAntibody-Dependent EnhancementArginineAttentionBindingCRISPR/Cas technologyCell LineCellsCharacteristicsCongenital AbnormalityCross InfectionDataDengue VirusDiseaseFlavivirusFlavivirus InfectionsGenesGenetic PolymorphismGenetic Predisposition to DiseaseGenotypeHumanHuman CloningIgG ReceptorsIgG1IgG2IgG3IgG4Immunoglobulin GIn VitroIndividualInfectionInternationalK-562K562 CellsMediatingMolecularMonoclonal AntibodiesPlacentaPositioning AttributeRisk FactorsSerotypingSeverity of illnessSingle Nucleotide PolymorphismTestingVariantViral Load resultVirus DiseasesZIKV infectionZika Virusbaseepidemiologic datahigh riskmacrophagemonocytemosquito-bornereceptorrepaired
项目摘要
PROJECT SUMMARY:
Antibody-dependent enhancement (ADE) is a phenomenon characteristic of some flavivirus infections and best
known to occur between the four DENV serotypes in humans, but may also occur between sequential DENV,
then ZIKV infections (or vice versa). ADE occurs when subneutralizing levels of antibodies raised against one
flavivirus infection cross-react to enhance a closely related flavivirus infection. ADE is entirely dependent on
the binding of IgG antibodies to FcRs found on susceptible cells, such as monocytes/macrophages. In
humans, there is a nonsynonymous polymorphism that occurs in the FcRIIA gene (rs1801274) that leads to
an arginine (Arg) to histadine (His) change at position 131 that has been shown to alter the affinity of this
receptor for IgG antibodies. We hypothesize that individuals homozygous for the FcRIIA encoding for the high
affinity His allele are at higher risk for developing ADE of flaviviruses than individuals homozygous for the low
affinity Arg allele. In this application, we will test this using K562 cells homozygous for the Arg131 or the
His131 allele as well as primary human monocytes stratified based on genotype to test how this SNP impacts
ADE of flaviviruses in vitro (Aim 1). Using two flavivirus-specific monoclonal antibody clones that we found to
enhance flavivirus infection in K562 cells, we will generate IgG subclass switch variants (IgG1, IgG2, IgG3, or
IgG4) to determine the relative contribution of each IgG subclass in mediating ADE of flaviviruses (Aim 2).
项目概要:
抗体依赖性增强(ADE)是一些黄病毒感染的特征性现象,
已知在人类的四种DENV血清型之间发生,但也可能在连续的DENV之间发生,
然后是ZIKV感染(反之亦然)。ADE发生时,亚中和水平的抗体对一个
黄病毒感染交叉反应以增强密切相关的黄病毒感染。ADE完全依赖于
IgG抗体与易感细胞(如单核细胞/巨噬细胞)上发现的Fc受体的结合。在
在人类中,Fc ε RIIA基因(rs 1801274)中存在非同义多态性,导致
位置131处的精氨酸(Arg)至组氨酸(His)的变化,其已显示改变了这种结合的亲和力。
IgG抗体的受体。我们假设,编码高表达的Fc ε RIIA的纯合子个体,
与低亲和力His等位基因纯合的个体相比,
亲和力Arg等位基因。在本申请中,我们将使用Arg 131纯合的K562细胞或
His 131等位基因以及基于基因型分层的原代人单核细胞,以测试该SNP如何影响
体外黄病毒的ADE(目的1)。使用我们发现的两种黄病毒特异性单克隆抗体克隆,
增强K562细胞中的黄病毒感染,我们将产生IgG亚类转换变体(IgG 1、IgG 2、IgG 3或IgG 4)。
IgG 4),以确定每个IgG亚类在介导黄病毒ADE中的相对贡献(目的2)。
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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Jean Kyou Lim其他文献
Jean Kyou Lim的其他文献
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{{ truncateString('Jean Kyou Lim', 18)}}的其他基金
Identification of the initial cells infected by West Nile virus ex vivo and in vivo
离体和体内西尼罗河病毒感染的初始细胞的鉴定
- 批准号:
10708949 - 财政年份:2022
- 资助金额:
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Identification of the initial cells infected by West Nile virus ex vivo and in vivo
离体和体内西尼罗河病毒感染的初始细胞的鉴定
- 批准号:
10595385 - 财政年份:2022
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Enhanced susceptibility to Zika virus during pregnancy: a role for maternal dengue antibodies
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10686827 - 财政年份:2020
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$ 25.36万 - 项目类别:
Enhanced susceptibility to Zika virus during pregnancy: a role for maternal dengue antibodies
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- 批准号:
10119036 - 财政年份:2020
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Enhanced susceptibility to Zika virus during pregnancy: a role for maternal dengue antibodies
怀孕期间对寨卡病毒的易感性增强:母体登革热抗体的作用
- 批准号:
10265599 - 财政年份:2020
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Enhanced susceptibility to Zika virus during pregnancy: a role for maternal dengue antibodies
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- 批准号:
10462665 - 财政年份:2020
- 资助金额:
$ 25.36万 - 项目类别:
Chemokine regulation of myeloid cell populations during West Nile virus infection
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8760176 - 财政年份:2014
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Chemokine regulation of myeloid cell populations during West Nile virus infection
西尼罗河病毒感染期间骨髓细胞群的趋化因子调节
- 批准号:
9313124 - 财政年份:2014
- 资助金额:
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Chemokine regulation of myeloid cell populations during West Nile virus infection
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8903793 - 财政年份:2014
- 资助金额:
$ 25.36万 - 项目类别:
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- 批准号:
8566428 - 财政年份:2013
- 资助金额:
$ 25.36万 - 项目类别:
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