Project-003

项目-003

• 批准号: 10170029
• 负责人: JEFFREY Victor RAVETCH
• 金额: $ 62.61万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-05 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10170029
• 关键词: 2019-nCoV; Adult Respiratory Distress Syndrome; Antibodies; Antibody Diversity; Antibody Response; Antibody Specificity; Antibody Therapy; Antigens; B-Cell Activation; B-Lymphocytes; Biological Assay; COVID-19; COVID-19 pandemic; Characteristics; Clinical; Clinical Data; Clonality; Development; Disease; Disease susceptibility; Fc domain; Heterogeneity; Human; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Immunologics; Individual; Infection; Life; Mediating; Memory B-Lymphocyte; Pathogenesis; Pathogenicity; Patient Recruitments; Patients; Phenotype; Pneumonia; Polysaccharides; Population; Predisposition; Property; Public Health; Receptors, Antigen, B-Cell; Research; Serological; Severity of illness; Specificity; Symptoms; Therapeutic Intervention; Virus; Virus Diseases; antiviral immunity; cohort; cross reactivity; disorder control; disorder prevention; epidemiologic data; follow-up; high risk population; insight; novel; novel therapeutics; parent grant; recruit; response; socioeconomics; transcriptome; transcriptomics; vaccine development

Abstract Extensive research on the basic immunological mechanisms that drive human immunity has provided the general framework by which the human immune system responds to foreign antigens. However, it is well-appreciated that each viral infection poses unique challenges to the immune system and the elicited immune responses are characterized by substantial heterogeneity that impacts disease susceptibility and pathogenesis, by conferring either protective or disease-enhancing activities. The ongoing COVID-19 pandemic represents a significant threat for global public health with tremendous socio-economic consequences. Early clinical and epidemiological data from COVID-19 patients suggest that while for the majority of the population, SARS-CoV-2 infection causes mild symptoms that usually resolve within a few weeks, a substantial fraction of patients develops severe, often life-threatening, clinical complications, including acute respiratory distress syndrome and pneumonia. Differences in the induction of protective antiviral immunity likely accounts for the differential susceptibility to severe disease upon SARS-CoV-2 infection. Understanding the heterogeneity of immune responses elicited upon SARS-CoV-2 infection is therefore critical for characterizing the immune mechanisms that confer protection against COVID-19 disease, guiding the development of novel therapeutics for disease control, as well as, determining disease susceptibility in high-risk populations. The proposed studies aim to characterize the antibody responses that are elicited upon infection with SARS-CoV-2, determining the breadth of antibody specificities, neutralization potency, as well as Fc domain heterogeneity of anti-SARS-CoV-2 IgG antibodies. More specifically, we plan to recruit recovered COVID-19 patients and systematically analyze their B-cell responses to determine their transcriptomic profile, as well as the functional properties of their B-cell receptors. In parallel, serologic studies from these individuals aim to characterize the breadth and potency of their neutralization activity and determine the subclass and Fc glycan distribution of anti-SARS-CoV-2 antibodies. Additionally, Fc domain function will be assessed in well-established ADCC, ADCP, and ADE assays to evaluate the capacity of anti-SARS-CoV-2 IgG antibodies to confer protective or pathogenic activities. Follow-up serologic studies will be performed in a large cohort of patients with variable disease severity, ranging from asymptomatic to severe symptomatic cases, to determine the functional activity of elicited anti-SARS-CoV-2 antibodies and assess their Fc domain heterogeneity and effector function. These studies are within the scope of our parent grant, as they are focused on the understanding of the immune responses that are elicited during viral infection. We anticipate that the findings of these studies will provide novel insights into the immunological mechanisms that confer protection or susceptibility to COVID-19 disease, accelerating our efforts for the development of vaccine or therapeutic interventions for the control of SARS-CoV-2 infection.

抽象的 关于驱动人类免疫力的基本免疫机制的广泛研究为一般提供了 人类免疫系统对外国抗原反应的框架。但是，这是充分欣赏的 每种病毒感染都对免疫系统构成了独特的挑战，引起的免疫反应是 以实质性的异质性为特征 保护性或增强疾病的活动。正在进行的共同19-19大流行代表着重要的 对全球公共卫生的威胁，带有巨大的社会经济后果。早期临床和流行病学 COVID-19患者的数据表明，尽管大多数人群，SARS-COV-2感染是原因 通常在几周内解决的轻度症状，大部分患者会出现严重的症状 威胁生命，临床并发症，包括急性呼吸窘迫综合征和肺炎。 保护性抗病毒免疫诱导的差异可能是对 SARS-COV-2感染后的严重疾病。了解引起的免疫反应的异质性 因此，在SARS-COV-2感染时，对于表征提供保护的免疫机制至关重要 针对Covid-19疾病，指导开发用于疾病控制的新型治疗剂，以及 确定高风险人群中的疾病易感性。拟议的研究旨在表征 SARS-COV-2感染后引起的抗体反应，确定抗体的广度 特异性，中和效力以及抗SARS-COV-2 IgG抗体的FC结构域异质性。 更具体地说，我们计划招募恢复的COVID-19患者，并系统地分析其B细胞 确定其转录组谱以及其B细胞受体的功能特性的响应。 同时，来自这些人的血清学研究旨在表征其的广度和效力 中和活性并确定抗SARS-COV-2抗体的亚类和FC聚糖分布。 此外，FC域功能将在已建立的ADCC，ADCP和ADE分析中进行评估以评估 抗SARS-COV-2 IgG抗体赋予保护性或致病活性的能力。随访血清学 研究将在疾病严重程度可变的大量患者中进行，范围从无症状 严重的有症状病例，以确定引起的抗SARS-COV-2抗体的功能活性和 评估其FC域的异质性和效应子功能。这些研究在我们父母的范围内 格兰特（Grant），因为它们专注于对病毒感染期间引起的免疫反应的理解。 我们预计这些研究的结果将为免疫机制提供新的见解 这种赋予了对199疾病的保护或易感性，加速了我们为发展的努力 用于控制SARS-COV-2感染的疫苗或治疗干预措施。