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.

摘要 对驱动人类免疫的基本免疫学机制的广泛研究提供了一般的 人体免疫系统对外来抗原作出反应的框架。然而，它受到了广泛的赞赏 每一种病毒感染都会对免疫系统构成独特的挑战，引发的免疫反应是 以影响疾病易感性和致病机制的实质上的异质性为特征的，通过赋予 无论是保护性活动还是增强疾病的活动。正在进行的新冠肺炎大流行代表着一种重大的 对全球公共卫生造成巨大社会经济后果的威胁。早期临床和流行病学 来自新冠肺炎患者的数据表明，虽然对大多数人来说，SARS-CoV-2感染会导致 通常在几周内缓解的轻微症状，相当一部分患者发展为严重的，通常 危及生命的临床并发症，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不同可能是导致不同的易感性的原因 SARS-CoV-2感染后的严重疾病。理解免疫反应的异质性 因此，SARS-CoV-2感染对表征提供保护的免疫机制至关重要 对抗新冠肺炎病，指导疾病控制新疗法的开发，以及， 确定高危人群的疾病易感性。拟议的研究旨在描述 感染SARS-CoV-2后引起的抗体反应，决定抗体的广度 抗SARS-CoV-2抗体的特异性、中和效力以及Fc结构域的异质性。 更具体地说，我们计划招募康复的新冠肺炎患者，并对他们的B细胞进行系统分析 以确定它们的转录图谱以及其B细胞受体的功能特性。 与此同时，这些人的血清学研究旨在表征他们的广度和效力 并测定抗SARS-CoV-2抗体的亚类和Fc糖链分布。 此外，将在成熟的ADCC、ADCP和ADE分析中评估Fc域功能，以评估 抗SARS-CoV-2抗体具有保护性或致病性的能力。随访血清学 研究将在一大批疾病严重程度不同的患者中进行，范围从无症状 对于有严重症状的病例，检测诱导的抗SARS-CoV-2抗体的功能活性和 评估其Fc结构域的异质性和效应器功能。这些研究都在我们父母的研究范围之内 他们专注于了解在病毒感染过程中引发的免疫反应。 我们预计，这些研究的结果将为免疫机制提供新的见解。 这赋予了我们对新冠肺炎疾病的保护或易感性，加快了我们对 控制SARS-CoV-2感染的疫苗或治疗干预措施。