Host Factors in Response to Therapeutic Monoclonal Antibodies and Vaccination

对治疗性单克隆抗体和疫苗接种的宿主因素

• 批准号: 10198426
• 负责人: Robert P. Kimberly
• 金额: $ 22.27万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-19 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198426
• 关键词: 2019-nCoV; Acceleration; Acute; Affect; Affinity; African; African American; Antibodies; Antibody Formation; Antibody Response; Antiviral Agents; Architecture; Award; Binding Sites; Biological Process; COVID-19; COVID-19 pandemic; CRISPR/Cas technology; Cell membrane; Consensus; Coupled; Data; Deep South; Detection; Development; Digestion; Disease; Effectiveness; European; Excision; Fc Receptor; Funding; Genes; Genetic; Genomics; Genotype; Goals; Host Defense; Human; Humoral Immunities; Immune; Immune response; Immunization; Individual; Infection; Infectious Agent; Integration Host Factors; Knowledge; Letters; Ligand Binding; Link; Lymphoid Cell; Mediating; Modeling; Myeloid Cells; Outcome; Parents; Patients; Persons; Phase; Phenotype; Population; Population Heterogeneity; Protocols documentation; Research; Resolution; SNP genotyping; Series; Signal Transduction; Single Nucleotide Polymorphism; Stratification; Structure; Technology; Therapeutic Monoclonal Antibodies; Therapeutic antibodies; Vaccination; Variant; Work; arm; biobank; cell type; cohort; ethnic minority population; genetic architecture; genetic variant; genome sequencing; genomic locus; innovation; nanopore; novel; paralogous gene; parent grant; precision medicine; predicting response; protein structure; receptor; receptor expression; receptor function; response; structural genomics; whole genome

PROJECT SUMMARY. Effective responses in Fc-dependent, antibody-mediated anti-viral host defense require efficient and productive interactions between the cell-type specific Fc receptors of the host and anti- SARS-CoV-2 antibody. The apparent lack of effective responses in some patients represents both an opportunity and a critical challenge to delineate the mechanistic basis for such differences. Genetic inquiry can identify the contributions that the host brings to these differences. Preliminary data, presented in our parent U01, indicate that nearly one-third of persons have structural variants (SV) in the classical Fc locus in addition to the prevalent single nucleotide polymorphisms affecting affinity of ligand binding, receptor mobility in the plane of the cell membrane and quantitative receptor expression. These larger SVs affect Fc receptors on both lymphoid and myeloid cell series, and nearly a third are uncharacterized in terms of genomic structure, resultant alterations in protein structure and impact on net biological function. Furthermore, persons of African- American heritage are over-represented in a number of these novel variant clusters. Current genotyping and whole genome sequencing efforts (eg, COVID-19 hg; COVIDhge) are unable to identify and define these SVs because of the segmental duplication of the FCGR locus with >98% homology of the paralogs. New, innovative technical approaches involving CRISPR/Cas9 targeted excision of the paralogs, coupled with long- read sequencing, now enable resolution of novel structural variations impacting biological function. Such knowledge will present the exceptional opportunity to enhance our understanding of disparities in COVID-19 disease, to anticipate the host response and potentially to adjust vaccination protocols. Accordingly, the goals of this supplement are to 1) immediately implement and apply our CRISPR/Cas9 digestion strategy and long- read sequence technology of Aim 1b to an expanded number of individuals originally proposed emphasizing ethnic minorities disproportionally affected by the COVID-19 pandemic, 2) expand the number of variant clusters to include all those found in African-American donors, 3) sequence the FCGR region in 100 patients with severe COVID-19 phenotype drawing on biospecimens drawn from across the Deep South, and 4) accelerate the analysis of sequencing data to identify the novel architectures and begin development of scalable genotyping strategies for detection of SVs and SNPs that are predicted to impact Fc receptor function/expression and influence the host response to acquired humoral immunity in both the acute and convalescent phases of disease. These goals will be enabled our COVID-19 Enterprise biobank and biospecimens from across the Deep South through our CTSA-driven CCTS Partner Network and will directly impact on our ability to identify individuals more or less likely to respond to effector antibody production.

项目总结。Fc依赖、抗体介导的抗病毒宿主防御中的有效应答 需要宿主的细胞型特异性Fc受体和抗-Fc受体之间有效和有效的相互作用 SARS-CoV-2抗体。一些患者明显缺乏有效的反应，这既是一种 这既是一个机遇，也是一个关键挑战，以确定造成这种差异的机制基础。遗传研究可以 找出主持人对这些差异的贡献。初步数据，在我们的母公司中提供 U01，表明近三分之一的人在经典Fc基因座上还存在结构变异(SV) 对于影响配体结合亲和力、受体迁移率的流行单核苷酸多态， 细胞膜的平面和受体的定量表达。这些较大的SVs影响Fc受体 淋巴系和髓系，近三分之一的细胞在基因组结构方面没有特征， 由此产生的蛋白质结构变化和对净生物功能的影响。此外，非洲人-- 在这些新奇的变异集群中，美国的遗产被过度代表。目前的基因分型和 全基因组测序工作(如新冠肺炎HG；COVIDHGE)无法识别和定义这些SV 这是因为FCGR基因座的节段性重复，与旁系亲属的同源性为98%。新的, 创新的技术方法涉及CRISPR/CAS9有针对性地切除对虾，再加上长时间的 阅读测序，现在能够解决影响生物功能的新结构变异。是这样的 知识将提供一个难得的机会，来增进我们对新冠肺炎差距的理解 疾病，以预测宿主的反应，并可能调整疫苗接种方案。因此，目标是 1)立即实施和应用我们的CRISPR/Cas9消化策略和长期- 目标1b的阅读序列技术对最初提出的更多的个体强调 受新冠肺炎疫情影响不成比例的少数民族，2)扩大变种数量 3)对100名患者的FCGR区域进行测序 严重的新冠肺炎表型利用了来自南方腹地的生物标本，以及4) 加快对测序数据的分析，以确定新的体系结构并开始开发 可扩展的基因分型策略用于检测预测影响Fc受体的SVS和SNPs 急性和慢性支气管炎患者获得性体液免疫的功能/表达及影响宿主反应 疾病的恢复期。这些目标将使我们的新冠肺炎企业生物库和 通过我们的CTSA驱动的CCTS合作伙伴网络来自整个南方腹地的生物群落，并将直接 影响我们识别个体的能力，或多或少可能对效应器抗体的产生产生反应。