Effect of an Fc Gamma Receptor Polymorphism on Antibody-Dependent Enhancement of Zika Virus Infection

Fc γ 受体多态性对寨卡病毒感染抗体依赖性增强的影响

基本信息

批准号：
10580030
负责人：
Marisa Goff
金额：
$ 4.61万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2021-03-17 至 2024-03-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10580030
关键词：
Acids Address Affect Affinity Alleles Amino Acid Substitution Amino Acids Animal Model Antibodies Antibody-Dependent Enhancement Arginine Binding CRISPR/Cas technology Cell Line Cell Separation Cells Central America Cross Reactions Data Dengue Hemorrhagic Fever Dengue Infection Dengue Shock Syndrome Dengue Virus Development Disease Disease Outbreaks Encapsulated Exhibits Flavivirus Flavivirus Infections Genetic Genetic Polymorphism Genetic Recombination Genotype Goals Growth Heterozygote Histidine Human IgG Receptors IgG1 IgG2 Immunity Immunoglobulin G Immunology In Vitro Individual Infection Integration Host Factors K562 Cells Macrophage Mediating Mentorship Monoclonal Antibodies Mus Myeloid Cells Nature Outcome Pathogenesis Placenta Population Population Genetics Positioning Attribute Predisposition Pregnancy Pregnant Women Primary Infection Public Health Research Personnel Risk Role Scientist Serotyping Severities Severity of illness Single Nucleotide Polymorphism Site South America Techniques Tissues Variant Viral Load result Virus Virus Diseases Work ZIKV infection Zika Virus adverse pregnancy outcome cross reactivity epidemiology study fetal monocyte multidisciplinary natural antibodies pathogen receptor response training opportunity virology

Acids Address Affect Affinity Alleles Amino Acid Substitution Amino Acids Animal Model Antibodies Antibody-Dependent Enhancement Arginine Binding CRISPR/Cas technology Cell Line Cell Separation Cells Central America Cross Reactions Data Dengue Hemorrhagic Fever Dengue Infection Dengue Shock Syndrome Dengue Virus Development Disease Disease Outbreaks Encapsulated Exhibits Flavivirus Flavivirus Infections Genetic Genetic Polymorphism Genetic Recombination Genotype Goals Growth Heterozygote Histidine Human IgG Receptors IgG1 IgG2 Immunity Immunoglobulin G Immunology In Vitro Individual Infection Integration Host Factors K562 Cells Macrophage Mediating Mentorship Monoclonal Antibodies Mus Myeloid Cells Nature Outcome Pathogenesis Placenta Population Population Genetics Positioning Attribute Predisposition Pregnancy Pregnant Women Primary Infection Public Health Research Personnel Risk Role Scientist Serotyping Severities Severity of illness Single Nucleotide Polymorphism Site South America Techniques Tissues Variant Viral Load result Virus Virus Diseases Work ZIKV infection Zika Virus adverse pregnancy outcome cross reactivity epidemiology study fetal monocyte multidisciplinary natural antibodies pathogen receptor response training opportunity virology

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项目摘要

PROJECT SUMMARY Antibody-dependent enhancement (ADE) is a phenomenon by which antibodies raised in response to a primary infection cross-react to a similar pathogen during a subsequent infection, resulting in increased viral load and severity of disease. ADE of Zika virus (ZIKV) infection by preexisting DENV antibodies has been hypothesized to play a role in the severe adverse pregnancy outcomes observed following congenital ZIKV infection. ADE is mediated by interactions between virus-bound IgG antibodies and Fc gamma receptors (FcRs) on host cells. In humans, a nonsynonymous single nucleotide polymorphism (SNP) in FCGR2A, rs1801274, results in an amino acid change at site 131 from arginine (Arg131) to histidine (His131) in the IgG-binding region of FcRIIA. Previous work in vitro has shown that cells expressing the His131 receptor variant bind human IgG1 and IgG2 with significantly higher affinity than those expressing the Arg131 receptor variant. We hypothesize that individuals homozygous for the high affinity His131 allele will be at greater risk for ADE of viral infection than individuals homozygous for the low affinity Arg131 allele. In this application, we will assess the effect of this SNP on ADE of ZIKV using cell lines derived from K562 cells that are homozygous for the Arg131 or His131 allele and primary human monocytes that will be stratified by genotype (Aim 1). We have also generated IgG subclass switch variants of a flavivirus-reactive monoclonal antibody that we will use to assess the role of each IgG subclass in mediating ADE of ZIKV through the different FcRIIA variants using His131 and Arg131 homozygous K562 cell lines, primary human monocytes, and Hofbauer cells isolated from full term human placentas (Aim 2). A comprehensive understanding of host genetic factors that affect susceptibility to ADE, including those described in this proposal, may help to identify populations at increased risk of developing severe disease as a result of ZIKV infection, particularly among pregnant women. The proposed project provides an excellent opportunity for training that encapsulates traditional virology and immunology techniques, professional development, and mentorship that will support the applicant’s growth as an independent academic scientist.

项目摘要抗体依赖性增强（ADE）是一种现象在随后的感染期间感染与类似病原体的交叉反应，导致病毒载量增加和疾病的严重程度。已经假设，已经存在的DENV抗体的Zika病毒（ZIKV）感染的ADE已被假设在先天性ZIKV感染后观察到的严重不良怀孕结局中发挥作用。 Ade是通过在宿主细胞上与病毒结合的IgG抗体和FC伽马受体（FCRS）之间的相互作用介导。在人类是FCGR2A中的非同义单核苷酸多态性（SNP），RS1801274，导致氨基在FCRIIA的IgG结合区域中，从精氨酸（ARG131）到组氨酸（His131）的位点131的酸变化。以前的体外的工作表明，表达HIS131受体变体的细胞将人IgG1和IgG2与比表达ARG131受体变体的亲和力要高得多。我们假设个人与个人相比低亲和力Arg131等位基因的纯合子。在此应用程序中，我们将评估此SNP对ADE的影响使用来自ARG131或HIS131等位基因的K562细胞衍生的细胞系的ZIKV 人类单核细胞将通过基因型进行分层（AIM 1）。我们还生成了IgG子类开关黄病毒反应性单克隆抗体的变体我们将用来评估每个IgG亚类在使用HIS131和ARG131纯合K562细胞通过不同的FCRIIA变体介导ZIKV的ADE 线，原代人单核细胞和霍夫鲍尔细胞从完整的人plecetas分离出来（AIM 2）。对影响ADE易感性的宿主遗传因素的全面理解，包括所描述的遗传因素在此提案中，可能有助于确定由于 ZIKV感染，特别是在孕妇中。拟议的项目为封装传统病毒学和免疫学技术，专业发展以及将支持申请人作为独立学术科学家的成长的遗产。