Genetic Susceptibility of Antibody-dependent Enhancement of Flaviviruses

黄病毒抗体依赖性增强的遗传易感性

• 批准号: 9815044
• 负责人: Jean Kyou Lim
• 金额: $ 25.36万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9815044
• 关键词: Affinity; Alleles; Amino Acids; Antibodies; Antibody-Dependent Enhancement; Arginine; Attention; Binding; CRISPR/Cas technology; Cell Line; Cells; Characteristics; Congenital Abnormality; Cross Infection; Data; Dengue Virus; Disease; Flavivirus; Flavivirus Infections; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Human; Human Cloning; IgG Receptors; IgG1; IgG2; IgG3; IgG4; Immunoglobulin G; In Vitro; Individual; Infection; International; K-562; K562 Cells; Mediating; Molecular; Monoclonal Antibodies; Placenta; Positioning Attribute; Risk Factors; Serotyping; Severity of illness; Single Nucleotide Polymorphism; Testing; Variant; Viral Load result; Virus Diseases; ZIKV infection; Zika Virus; base; epidemiologic data; high risk; macrophage; monocyte; mosquito-borne; receptor; repaired

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 FcRs found on susceptible cells, such as monocytes/macrophages. In humans, there is a nonsynonymous polymorphism that occurs in the FcRIIA 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 FcRIIA 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).

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