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众健康有重大影响， 对世界上很大一部分人口的社会经济影响。大量的流行病学数据 表明对登革热的易感性与既往的黄病毒感染密切相关，这意味着 作为主要疾病决定因素的交叉反应、非中和抗体的存在。这一观察结果已经 已在动物疾病模型中得到证实，在动物疾病模型中，被动注射黄病毒免疫血清或黄病毒- 反应性单抗增加了疾病的严重性，并导致了死亡率的增加。活体内的这些 研究表明，抗体的致病活性依赖于其Fc结构域的能力 与Fcγ受体(Fcγ受体)相互作用。目前被接受的交叉反应的机理模型 抗体对疾病病理的贡献是基于体外观察到的免疫球蛋白抗体介导的 FcγR依赖株中病毒-免疫球蛋白复合物摄取增加对FcγR表达细胞的感染 举止。这一现象已经在使用原代细胞或细胞系的体外分析中得到证实。 仅表达一组有限的人类FcγR的髓系血统。这样的实验条件并不准确 反映体内存在的表达FcγR的效应器白细胞的复杂性和多样性，目前尚不清楚 这些实验观察可能与致病抗体的生物学活性有关 动物疾病模型和人类种群。更重要的是，这种简单化的模型不足以 解释为什么有症状的登革热表现出如此不同的临床表型 病情严重，只有一小部分有症状的登革热患者进展为重症 最终死于死亡。显然，存在影响登革热的复杂宿主易感因素。 发病机制和确定疾病严重程度。到目前为止，还没有系统分析FcγRs在抗体中的作用。 在登革热感染期间进行了介导性疾病增强，并准确地贡献了 FcγR介导的通路在很大程度上是未知的，主要是由于缺乏强大的体内模型系统 这正好反映了人类FcγR生物学的独特复杂性。拟议的研究旨在剖析 Fc-FcγR相互作用在体内介导ADE的机制及其Fc效应功能 对登革热的易感性和严重性。我们预计，我们的发现将大大推进我们的 了解登革热的发病机制，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。

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.