Core C: Immunoglobulin Proteomics in COVID-19

核心 C：COVID-19 中的免疫球蛋白蛋白质组学

• 批准号: 10222243
• 负责人: GREGORY C IPPOLITO
• 金额: $ 81.59万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222243
• 关键词: 2019-nCoV; Abate; Advisory Committees; Affinity; Antibodies; Antibody Repertoire; Antibody Response; Antiviral Agents; Area; B cell repertoire; B-Lymphocytes; Binding; Biological Assay; Blood Circulation; COVID-19; Categories; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical Trials; Clonality; Cloning; Computerized Medical Record; Coronavirus; County; Data; Data Set; Disease; Disease Outbreaks; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Epitopes; Future; Geographic state; Half-Life; Home environment; Human; Immune; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; Individual; Infection; Institutional Review Boards; Kinetics; Letters; Masks; Methodology; Middle East Respiratory Syndrome Coronavirus; Molecular; Molecular Analysis; Monitor; Monoclonal Antibodies; Mucous Membrane; Natural History; Nature; North Carolina; Outcomes Research; Patients; Pattern; Phase; Plasma; Policies; Population; Prevalence; Proteins; Proteomics; Protocols documentation; Research; Resolution; Role; SARS coronavirus; Scourge; Serologic tests; Serological; Serum; Source; Specificity; Specimen; Study Subject; Survivors; Symptoms; Techniques; Testing; Texas; Time; Transfusion; Translating; Viral; Virus; Work; Zoonoses; austin; base; cohort; comparative; cross reactivity; experimental study; human monoclonal antibodies; in vivo; mouse model; neutralizing antibody; neutralizing monoclonal antibodies; pandemic disease; response; sample collection; social; virtual

Abstract Research Core C will be integral to the examination of serological antibody repertoires in COVID-19 study subjects as well as in convalescent plasmas obtained from survivors. Core C will employ a set of unique experimental techniques including a proteomic methodology (Ig-seq) for the identification of the monoclonal sequences and for determining the epitope specificity and function of the secreted component immunoglobulins (IgG and IgA) comprising the polyclonal response to SARS-CoV-2. The UT Core will examine the persistence of individual serum mAb clonotypes as a function of time and also the relationships between the IgA and IgG repertoires in circulation and in BAL. To date, all human SARS-CoV-2-reactive antibodies have been isolated exclusively from B cells transiently circulating in the periphery. The significance of the abundance, durability, and interconnectivity of serological antibodies—IgG versus IgA, neutralizing versus non-neutralizing, mucosal versus systemic—shall become clear as this research core comprehensively analyzes the molecular composition of anti-viral IgG and IgA and traces the B-cell subpopulations from which they arose. These studies will be enabled by robust sample collections from UNC Chapel Hill and from UT Austin. We expect that the experimental outcomes of Research Core C will clarify (i) the extent of antibody breadth and potency of the constituent IgG and IgA in the serological repertoires and role in protection (via viral blockade or through Fc dependent mechanisms) against endemic and zoonotic coronaviruses in mouse models (Project 1), and (ii) the detailed molecular-level characterization of convalescent plasmas used for transfusion therapy in a COVID-19 clinical trial (Project 2). Comparative analyses shall be performed to determine adaptive immune signatures which may explain differential patterns among asymptomatic, oligosymptomatic, and severe disease. This research will be critical to our understanding the nature and complexity of human antibody responses against the SARS-CoV-2 pandemic scourge.

抽象的 研究核心C将是COVID-19研究中血清学抗体库的检查不可或缺的一部分 受试者以及从幸存者获得的疗养等离子体中。核心C将采用一组独特的 实验技术，包括用于鉴定单克隆的蛋白质组学方法（IG-SEQ） 序列和确定分泌组件免疫球蛋白的表位特异性和功能 （IgG和IgA）完成对SARS-COV-2的多克隆响应。 UT核心将检查 单个血清mAb clonotypes作为时间的函数以及IgA和IgG之间的关系 流通和BAL中的曲目。迄今为止，已经隔离了所有人类SARS-COV-2反应抗体 仅来自B细胞的B细胞在周围瞬时循环。丰度，耐用性和 血清学抗体的互连性 - IGG与IgA，中和与非中和化，粘膜与 系统性 - 随着该研究核心全面分析的分子组成，因此变得很清楚 抗病毒IgG和IgA并追踪其出现的B细胞亚群。这些研究将启用 通过UNC Chapel Hill和UT Austin的强大样品收集。我们期望实验 研究核心C的结果将澄清（i）组成IgG的抗体宽度和效力的程度 和IgA在血清学曲目和保护中的作用（通过病毒阻滞或通过FC依赖性 机理）反对小鼠模型中的内在和人畜共努性冠状病毒（项目1），以及（ii）详细的 用于输血疗法的康复等离子体的分子水平表征在COVID-19临床中 试验（项目2）。应进行比较分析以确定可能的适应性免疫特征 解释渐近，寡聚和严重疾病的差异模式。这项研究将是 对我们理解人类抗体反应的性质和复杂性至关重要 大流行祸害。