Fc domain effector activity in dengue disease

登革热疾病中的 Fc 结构域效应子活性

• 批准号: 10595526
• 负责人: JEFFREY Victor RAVETCH
• 金额: $ 58.61万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595526
• 关键词: Affinity; Antibodies; Antibody-Dependent Enhancement; Antigenic Specificity; Area; Blood Platelets; Blood Vessels; Cell Line; Cessation of life; Characteristics; Clinical; Complex; Dengue; Dengue Fever; Dengue Hemorrhagic Fever; Dengue Infection; Disease; Disease susceptibility; Engineering; Exhibits; Extravasation; Family; Fc domain; Fever; Flavivirus; Flavivirus Infections; Hemorrhagic Shock; Human; Human Activities; IgG1; Immune; Immune response; Immunity; Immunoglobulin G; In Vitro; Individual; Infection; Inflammatory; Influenza vaccination; Leukocytes; Life; Mediating; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Polysaccharides; Population; Predisposition; Primary Infection; Public Health; Recording of previous events; Risk Factors; Role; Seroprevalences; Severities; Severity of illness; Shock; Structure; Symptoms; Syndrome; Testing; Thrombocytopenia; Vaccines; Variant; Virus; West Nile; Yellow Fever; ZIKA; clinical phenotype; cohort; cross reactivity; epidemiologic data; epidemiology study; follow-up; high risk; humanized mouse; immunoregulation; in vivo; insight; mouse model; novel; prevent; receptor; response; severe dengue; socioeconomics; uptake; vaccine response

ABSTRACT – Project 1, Ravetch Flaviviruses, such as dengue, Zika, and West Nile have a significant impact on public health with tremendous socioeconomic consequences for a large fraction of the world's population. A feature common to all flaviviruses is the clear distinction between infection and disease. For example, only a small fraction of dengue-infected individuals develops dengue disease, which is characterized by a diverse spectrum of clinical symptoms of variable severity. A large body of epidemiological data suggests that prior flavivirus infection represents the major risk factor for dengue disease susceptibility. Indeed, susceptibility to severe dengue disease is associated with the titers of cross-reactive, non-neutralizing IgG antibodies that are elicited during primary infection with other flaviviruses. The established mechanistic model by which IgG antibodies contribute to disease susceptibility is based upon the in vitro observation that these antibodies mediate infection of leukocytes through increased uptake of virus-IgG complexes via specific interactions of their Fc domains with Fcγ receptors (FcγRs); a phenomenon termed antibody-dependent enhancement (ADE) of infection. Although this model can sufficiently explain susceptibility to dengue disease, it is likely that complex host susceptibility factors exist that contribute to disease pathogenesis and determine severity among symptomatic dengue patients. Consistent with this hypothesis, our recent analysis of the Fc domain structure of IgG antibodies derived from dengue patients with variable disease severity revealed that specific Fc domain characteristics that confer increased affinity for pro- inflammatory, activating FcγRs, are enriched in patients with severe disease and evidence for specific clinical manifestations, including thrombocytopenia and vascular leakage. These antibodies exacerbate disease severity by inducing platelet depletion via FcγR-mediated mechanisms, suggesting that previously-uncharacterized ADE mechanisms contribute to disease pathology. Understanding the mechanisms that mediate dengue ADE is essential for predicting the susceptibility to severe dengue disease in high-risk patient groups and developing approaches to prevent or reduce disease-associated clinical manifestations. In the proposed studies, we will analyze the IgG responses from cohorts of dengue-infected patients with variable disease severity to identify the specific IgG features that are associated with dengue disease severity and clinical manifestations. Follow-up mechanistic studies in mouse models of dengue disease using strains fully humanized for all classes of FcγRs will be performed to determine the role of specific human FcγRs in dengue disease and characterize the precise FcγR pathways that contribute to disease pathogenesis. Lastly, we will characterize IgG responses elicited upon influenza vaccination of individuals with differential susceptibility to severe flavivirus infection to determine whether changes in the Fc domain structure represent immune determinants for predicting disease susceptibility. Our studies will provide novel insights into the mechanisms by which pathogenic IgG antibodies mediate dengue disease and have a broader impact on our understanding of the pathogenesis of other flaviviruses, like Zika.

摘要 – 项目 1，Ravetch 黄病毒，例如登革热、寨卡病毒和西尼罗河病毒对公共健康具有巨大影响 对世界上很大一部分人口造成的社会经济后果。所有黄病毒共有的特征 是感染和疾病之间的明显区别。例如，只有一小部分感染登革热的人 个体患有登革热病，其特征是多种临床症状 严重程度可变。大量流行病学数据表明，先前的黄病毒感染是主要的原因。 登革热易感性的危险因素。事实上，对严重登革热疾病的易感性与 交叉反应性、非中和性 IgG 抗体的滴度，这些抗体是在初次感染其他病毒时引起的 黄病毒。已建立的 IgG 抗体导致疾病易感性的机制模型是 根据体外观察，这些抗体通过增加白细胞介导的感染 通过其 Fc 结构域与 Fcγ 受体 (FcγR) 的特异性相互作用来摄取病毒-IgG 复合物；一个 这种现象被称为抗体依赖性感染增强（ADE）。虽然这个模型足以 为了解释对登革热疾病的易感性，很可能存在复杂的宿主易感性因素，这些因素有助于 确定疾病发病机制并确定有症状的登革热患者的严重程度。与此一致 假设，我们最近对来自登革热患者的 IgG 抗体的 Fc 结构域结构进行了分析 不同的疾病严重程度表明，特定的 Fc 结构域特征赋予亲和力增加 炎症、激活 FcγR 在患有严重疾病的患者中丰富，并且有特定临床证据 表现，包括血小板减少和血管渗漏。这些抗体会加剧疾病的严重程度 通过 FcγR 介导的机制诱导血小板耗竭，这表明以前未表征的 ADE 机制有助于疾病病理学。了解介导登革热 ADE 的机制 对于预测高危患者群体对严重登革热疾病的易感性和发展至关重要 预防或减少疾病相关临床表现的方法。在拟议的研究中，我们将 分析不同疾病严重程度的登革热感染患者群体的 IgG 反应，以确定 与登革热疾病严重程度和临床表现相关的特定 IgG 特征。跟进 使用针对所有类别 FcγR 完全人源化的菌株对登革热疾病小鼠模型进行机制研究 将进行以确定特定人类 FcγR 在登革热疾病中的作用并表征精确的 FcγR 通路有助于疾病发病机制。最后，我们将描述 IgG 反应的特征 对严重黄病毒感染具有不同易感性的个体进行流感疫苗接种，以确定 Fc 结构域结构的变化是否代表预测疾病易感性的免疫决定因素。 我们的研究将为致病性 IgG 抗体介导登革热的机制提供新的见解 疾病，并对我们对其他黄病毒（如寨卡病毒）发病机制的理解产生更广泛的影响。