Mechanisms of Antibody-Dependent Enhancement of Dengue Disease

摘要 寨卡病毒、登革热病毒和西尼罗河病毒等黄病毒对公共卫生具有重大影响 对世界上很大一部分人口造成的社会经济后果。大量流行病学数据 表明对登革热疾病的易感性与先前的黄病毒感染密切相关，这意味着 交叉反应性、非中和性抗体的存在是主要的疾病决定因素。这一观察有 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- 反应性单克隆抗体加剧了疾病的严重程度并导致死亡率增加。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 (FcγR) 相互作用。目前公认的交叉反应机制模型 抗体对疾病病理学的贡献基于 IgG 抗体介导的体外观察 通过增加 FcγR 依赖性病毒-IgG 复合物的摄取来感染 FcγR 表达细胞 方式。这种现象已在使用原代细胞或细胞系的体外测定中得到证实。 仅表达一组有限的人类 FcγR 的骨髓谱系。这样的实验条件并不能准确 反映了体内存在的表达 FcγR 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致病性抗体的生物活性有关 动物疾病模型和人群。更重要的是，这种简单化的模型并不能充分 解释为什么有症状的登革热病表现出如此多样化的临床表型 疾病严重程度，只有一小部分有症状的登革热患者进展为严重疾病 并最终屈服于死亡。显然，存在影响登革热的复杂宿主易感因素 发病机制并确定疾病的严重程度。迄今为止，还没有系统分析FcγR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，并且精确的贡献 FcγR 介导的途径很大程度上未知，这主要是由于缺乏强大的体内模型系统 这将准确地反映人类 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 的机制以及贡献的 Fc 效应子功能 登革热疾病的易感性和严重程度。我们预计我们的发现将显着推进我们的研究 了解登革热疾病的发病机制，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。

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.