Mechanisms of Antibody-Dependent Enhancement of Dengue Disease

登革热病抗体依赖性增强机制

• 批准号: 10462721
• 负责人: Stylianos Bournazos
• 金额: $ 42.38万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462721
• 关键词: Affinity; Animal Disease Models; Antibodies; Antibody-Dependent Enhancement; Antigenic Specificity; Area; Biological; Biological Models; Biology; Cell Line; Cells; Cessation of life; Characteristics; Clinical; Complex; Dengue; Dengue Fever; Dengue Hemorrhagic Fever; Dengue Infection; Development; Disease; Disease susceptibility; Engineering; Exhibits; Fc domain; Fever; Flavivirus; Flavivirus Infections; Genetically Engineered Mouse; Hemorrhagic Shock; Human; Human Activities; Immune Sera; Immunoglobulin G; Immunologic Factors; In Vitro; Individual; Infection; Leukocytes; Life; Mediating; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mouse Strains; Mus; Myelogenous; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Population; Predisposition; Property; Public Health; Risk Factors; Role; Sampling; Seroprevalences; Severities; Severity of illness; Shock; Signal Transduction; Syndrome; System; Variant; Virus; West Nile virus; Yellow Fever; ZIKA; base; clinical phenotype; cohort; cross reactivity; epidemiologic data; epidemiology study; high risk; human disease; humanized mouse; in vitro Assay; in vivo; in vivo Model; insight; mortality; novel; prevent; receptor; receptor binding; receptor function; socioeconomics; stem; therapeutic development; uptake; zika fever

ABSTRACT Flaviviruses, such as Zika, dengue and West Nile have significant impact on public health with tremendous socioeconomic consequences for a large fraction of the world's population. A large body of epidemiological data suggests that susceptibility to dengue disease is strongly associated with prior flavivirus infection, implicating the presence of cross-reactive, non-neutralizing antibodies as the major disease determinant. This observation has been confirmed in animal disease models, in which passive administration of flavivirus immune sera or flavivirus- reactive monoclonal antibodies enhanced disease severity and resulted in increased mortality. These in vivo studies revealed that the pathogenic activity of antibodies is dependent upon the capacity of their Fc domains to interact with Fcγ receptors (FcγRs). The currently accepted mechanistic model by which cross-reactive antibodies contribute to disease pathology is based upon the in vitro observation that IgG antibodies mediate infection of FcγR-expressing cells through increased uptake of virus-IgG complexes in an FcγR-dependent manner. This phenomenon has been demonstrated in in vitro assays using primary cells or cell lines of the myeloid lineage that express only a limited set of human FcγRs. Such experimental conditions do not accurately reflect the complexity and diversity of FcγR-expressing effector leukocytes present in vivo and it is unclear how these experimental observations could be related to the biological activities of pathogenic antibodies evident in animal disease models and in human populations. More importantly, this simplistic model cannot sufficiently explain why symptomatic dengue disease exhibits so diverse spectrum of clinical phenotypes with varying disease severity and only a small fraction of symptomatic dengue disease patients progress to severe disease and ultimately succumbs to death. It is evident that complex host susceptibility factors exist that influence dengue pathogenesis and determine disease severity. So far, no systematic analysis of the role of FcγRs in the antibody- mediated disease enhancement during dengue infection has been performed and the precise contribution of FcγR-mediated pathways is largely unknown, stemming primarily from the lack of a robust in vivo model system that would mirror precisely the unique complexity of human FcγR biology. The proposed studies aim to dissect the mechanisms by which Fc-FcγR interactions mediate ADE in vivo and the Fc effector functions that contribute to dengue disease susceptibility and severity. We anticipate that our findings will significantly advance our understanding of dengue disease pathogenesis and will have broader impact on the study of other flaviviruses, like Zika and yellow fever.

摘要 黄病毒，如寨卡病毒、登革热和西尼罗河病毒对公共卫生有重大影响， 对世界上很大一部分人口的社会经济后果。大量的流行病学数据 提示登革热易感性与先前的黄病毒感染密切相关，提示 交叉反应性非中和抗体的存在是主要的疾病决定因素。此观察结果 在动物疾病模型中得到证实，其中被动施用黄病毒免疫血清或黄病毒- 反应性单克隆抗体增强了疾病的严重性并导致死亡率增加。这些体内 研究表明，抗体的致病活性取决于其Fc结构域的能力， 与Fcγ受体（FcγRs）相互作用。目前公认的机制模型，其中交叉反应 抗体对疾病病理学的贡献是基于体外观察，IgG抗体介导 通过增加Fcγ R依赖性细胞中病毒-IgG复合物的摄取感染Fcγ R表达细胞 方式这种现象已经在使用本发明的原代细胞或细胞系的体外测定中得到证实。 仅表达有限的一组人Fcγ R的骨髓谱系。这样的实验条件并不准确。 反映了体内表达Fcγ R的效应白细胞的复杂性和多样性，目前尚不清楚如何 这些实验观察结果可能与病原体抗体的生物活性有关， 动物疾病模型和人群中。更重要的是，这种简单化的模式不能充分地 解释为什么有症状的登革热病表现出如此多样的临床表型谱， 疾病的严重程度，只有一小部分有症状的登革热患者进展为严重疾病 最后还是死了很明显，存在影响登革热的复杂宿主易感性因素 发病机制和确定疾病的严重程度。到目前为止，还没有系统分析Fcγ R在抗体中的作用- 登革热感染期间介导的疾病增强已经进行， Fcγ R介导的途径在很大程度上是未知的，主要源于缺乏稳健的体内模型系统 这将精确地反映人类FcγR生物学的独特复杂性。拟议的研究旨在剖析 Fc-FcγR相互作用介导体内ADE的机制和Fc效应子功能， 登革热的易感性和严重性。我们预计，我们的发现将大大推动我们的 了解登革热病的发病机制，并将对其他黄病毒的研究产生更广泛的影响， 比如寨卡病毒和黄热病