Mechanisms of Antibody-Dependent Enhancement of Dengue Disease

摘要 登革热病毒(DENV)的免疫球蛋白抗体不是提供保护，而是与 对有症状的登革热的易感性增加，因为患者已经存在针对DENV的抗体 有症状的登革热发病率较高，通常包括危及生命的疾病 并发症。超过25亿人面临感染登革热病毒的风险，并有1亿新感染者 每年发生的DENV对全球人类公共卫生构成巨大负担，需要 开发有效的治疗或疫苗接种方法来控制DENV感染和疾病。vbl.使用 在体外细胞分析中，先前的几项研究表明，抗DENV抗体可以介导 增强表达Fcγ受体(FcγR)的髓系细胞的病毒感染；这种现象称为抗体 依赖性增强(ADE)。然而，病毒复制的ADE本身不能解释这种复杂性 有症状的登革热的病理生理学特征以及广泛的临床疾病 在有症状的患者中观察到严重程度。在上一次供资期间，在与 在登革热流行地区柬埔寨的巴斯德研究所，我们证明了登革热的易感性， 以及疾病的严重程度与诱导特定糖型的免疫球蛋白抗体有关 (果糖基化)，表现出与激活的FcγRIII受体的亲和力增加。在平行的机械学研究中， 我们开发了一种新的登革热体内模型，它表达了人类Fc、γ、Rs和IS的完整阵列 允许感染登革热病毒。利用这个模型，我们证明了体内发病机制中的一个关键步骤 登革热的致病因素是FcγRIIIa通过果糖基化的免疫球蛋白抗体与巨噬细胞结合，这些抗体是 在严重的登革热病例中丰富。Fc-γRIIIa-Fucosylated Ig G抗体相互作用导致巨噬细胞异常 激活、炎症性后遗症、显著发病率和死亡率。这些发现表明，FCγRIIIA- Fc轴作为登革热易感性和发病机制的基础。使用一组独特的 来自DENV感染患者的生物旋毛虫，以及我们最近开发的登革热ADE小鼠模型 关于疾病，建议的研究目的是：(I)剖析诱导免疫球蛋白Fc果糖基化的机制 DENV感染时的糖形式和(Ii)表征在感染后启动的下游效应器反应 Fc-γRIIIa与Fc-Ig G抗体结合，参与疾病的发病。我们期待着 我们的发现将极大地促进我们对调节免疫球蛋白Fc多糖的途径的理解 在DENV感染期间的异质性和驱动登革热疾病的发病机制，对 对以异常的Ig G Fc岩藻糖化为特征的其他病毒病原体的免疫应答的研究。

ABSTRACT Instead of conferring protection, IgG antibodies against dengue virus (DENV) have been correlated with increased susceptibility to symptomatic dengue disease, as patients with pre-existing antibodies against DENV experience at a higher rate the symptomatic form of dengue disease, which often includes life-threatening complications. With over 2.5 billion people being at risk of DENV infection and with >100 million new infections occurring annually, DENV represents a tremendous burden to global human public health, necessitating the development of efficacious therapeutic or vaccination approaches to control DENV infection and disease. Using in vitro cellular assays, several studies have previously suggested that anti-DENV antibodies can mediate enhanced viral infection of Fcγ receptor (FcγR)-expressing myeloid cells; a phenomenon referred to as antibody dependent enhancement (ADE). However, ADE of viral replication alone cannot account for the complex pathophysiological features of symptomatic dengue disease, as well as for the wide spectrum of clinical disease severity observed among symptomatic patients. During the previous funding period, in collaborative studies with the Institute Pasteur in Cambodia, a DENV endemic area, we demonstrated that dengue disease susceptibility, as well as disease severity are associated with the induction of specific glycoforms of IgG antibodies (afucosylated) that exhibit increased affinity for the activating FcγRIII receptor. In parallel mechanistic studies, we developed a novel in vivo model of dengue disease that expresses the full array of human FcγRs and is permissive for DENV infection. Using this model, we demonstrated that a critical step in the in vivo pathogenesis of dengue disease is the engagement of FcγRIIIa on macrophages by afucosylated IgG antibodies, which are enriched in severe dengue cases. FcγRIIIa-afucosylated IgG antibody interactions result in aberrant macrophage activation, inflammatory sequelae, significant morbidity, and mortality. These findings implicate the FcγRIIIa- afucosylated Fc axis as the basis for dengue disease susceptibility and pathogenesis. Using a unique set of biospecimens from DENV-infected patients, as well as our recently developed mouse models of ADE of dengue disease, the proposed studies aim to (i) dissect the mechanisms that drive the induction of IgG Fc afucosylated glycoforms upon DENV infection and (ii) characterize the downstream effector responses that are initiated upon engagement of FcγRIIIa by afucosylated IgG antibodies and contribute to disease pathogenesis. We anticipate that our findings will significantly advance our understanding of the pathways that regulate IgG Fc glycan heterogeneity during DENV infection and drive dengue disease pathogenesis, having a broader impact on the study of immune responses against other viral pathogens that are characterized by aberrant IgG Fc fucosylation.