Fc domain effector activity in dengue disease

摘要-项目1，Ravetch 黄病毒，如登革热、寨卡病毒和西尼罗河病毒，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。所有黄病毒的共同特征 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 个人患上登革热，其特征是临床症状多种多样 严重程度可变。大量的流行病学数据表明，先前的黄病毒感染是主要的 登革热易感性的危险因素。事实上，对严重登革热的易感性与 在与其他人初次感染期间产生的交叉反应、非中和抗体滴度 黄病毒。已建立的免疫球蛋白抗体促进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 通过其Fc结构域与Fcγ受体(FcγR)的特异性相互作用摄取病毒免疫球蛋白复合体；a 这种现象被称为抗体依赖的感染增强(ADE)。尽管该模型可以充分地 解释登革热的易感性，很可能存在复杂的宿主易感因素 以确定有症状的登革热患者的疾病发病机制和严重程度。与此一致 假设，我们最近对来自登革热患者的免疫球蛋白抗体Fc区结构的分析 不同的疾病严重程度表明，特定的Fc结构域特征，赋予增加亲和力- 炎症，激活Fcγ受体，在重症患者中丰富，并为特定的临床证据 临床表现包括血小板减少和血管渗漏。这些抗体加重了疾病的严重性。 通过FcγR介导的机制诱导血小板耗竭，表明以前未描述的ADE 机制对疾病病理有贡献。了解介导登革热ADE的机制是 对预测高危人群中严重登革热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。在建议的研究中，我们会 分析不同疾病严重程度的登革热感染患者的免疫球蛋白反应，以确定 与登革热严重程度和临床表现相关的特异性免疫球蛋白特征。跟进 所有Fc-γ受体完全人源化菌株在登革热小鼠模型中的机制研究 将被用来确定特定的人类Fcγ受体在登革热疾病中的作用，并表征准确的 参与疾病发病机制的Fc-γ-R通路。最后，我们将描述在以下情况下引发的免疫球蛋白反应 流感疫苗接种对严重黄病毒感染易感性不同个体的确定 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免疫球蛋白抗体介导登革热的机制提供新的见解。 并对我们了解寨卡病毒等其他黄病毒的发病机制产生了更广泛的影响。

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.