Fc domain effector activity in dengue disease

摘要-项目1，Ravetch 黄病毒，如登革热、寨卡和西尼罗河病毒，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。所有黄病毒的共同特征 感染和疾病之间的明显区别例如，只有一小部分登革热感染者 个体发展成登革热病，其特征在于多种多样的临床症状， 可变严重度。大量流行病学数据表明，既往黄病毒感染是主要的 登革热易感性的危险因素。事实上，对严重登革热病的易感性与以下因素有关： 在原发性感染期间引起的交叉反应性、非中和性IgG抗体的滴度 黄病毒已建立的IgG抗体导致疾病易感性的机制模型是 基于体外观察这些抗体通过增加白细胞的增殖介导白细胞的感染 通过Fc结构域与Fcγ受体（Fcγ R）的特异性相互作用摄取病毒-IgG复合物; a 抗体依赖性感染增强（ADE）。虽然这种模式可以充分 解释对登革热病的易感性，可能存在复杂的宿主易感性因素， 疾病的发病机制，并确定有症状的登革热患者的严重程度。符合本 假设，我们最近分析了来自登革热患者的IgG抗体的Fc结构域结构， 不同的疾病严重程度揭示了特定的Fc结构域特征，赋予增加的亲合性， 炎症性、活化性Fcγ R在严重疾病患者中富集， 临床表现包括血小板减少和血管渗漏。这些抗体会加重疾病的严重程度 通过Fcγ R介导的机制诱导血小板耗竭，表明先前未表征的ADE 机制有助于疾病病理学。了解介导登革热ADE的机制是 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 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 分析来自不同疾病严重程度的登革热感染患者队列的IgG应答， 与登革热疾病严重程度和临床表现相关的特异性IgG特征。后续行动 使用所有类别Fcγ R完全人源化的菌株在登革热病小鼠模型中进行的机制研究 确定特异性人Fcγ R在登革疾病中的作用，并表征 FcγR通路有助于疾病的发病机制。最后，我们将描述IgG反应引起的 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， 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，并对我们理解其他黄病毒的发病机制产生更广泛的影响，如寨卡病毒。

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.