Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America.
PLoS Pathog. 2010 Feb 12;6(2):e1000790. doi: 10.1371/journal.ppat.1000790.
Immunity to one of the four dengue virus (DV) serotypes can increase disease severity in humans upon subsequent infection with another DV serotype. Serotype cross-reactive antibodies facilitate DV infection of myeloid cells in vitro by promoting virus entry via Fcgamma receptors (FcgammaR), a process known as antibody-dependent enhancement (ADE). However, despite decades of investigation, no in vivo model for antibody enhancement of dengue disease severity has been described. Analogous to human infants who receive anti-DV antibodies by transplacental transfer and develop severe dengue disease during primary infection, we show here that passive administration of anti-DV antibodies is sufficient to enhance DV infection and disease in mice using both mouse-adapted and clinical DV isolates. Antibody-enhanced lethal disease featured many of the hallmarks of severe dengue disease in humans, including thrombocytopenia, vascular leakage, elevated serum cytokine levels, and increased systemic viral burden in serum and tissue phagocytes. Passive transfer of a high dose of serotype-specific antibodies eliminated viremia, but lower doses of these antibodies or cross-reactive polyclonal or monoclonal antibodies all enhanced disease in vivo even when antibody levels were neutralizing in vitro. In contrast, a genetically engineered antibody variant (E60-N297Q) that cannot bind FcgammaR exhibited prophylactic and therapeutic efficacy against ADE-induced lethal challenge. These observations provide insight into the pathogenesis of antibody-enhanced dengue disease and identify a novel strategy for the design of therapeutic antibodies against dengue.
对四种登革热病毒 (DV) 血清型中的一种产生免疫力，可在人类随后感染另一种 DV 血清型时增加疾病的严重程度。血清型交叉反应性抗体通过促进 Fcγ 受体 (FcγR) 介导的病毒进入，促进 DV 感染髓样细胞，这一过程称为抗体依赖性增强 (ADE)。然而，尽管经过几十年的研究，仍未描述用于增强登革热疾病严重程度的体内抗体模型。类似于通过胎盘转移获得抗-DV 抗体并在初次感染时发生严重登革热的人类婴儿，我们在这里展示，通过被动给予抗-DV 抗体，使用适应小鼠的和临床分离的 DV 株，足以增强小鼠的 DV 感染和疾病。抗体增强的致死性疾病具有人类严重登革热的许多特征，包括血小板减少症、血管渗漏、血清细胞因子水平升高以及血清和组织吞噬细胞中系统性病毒载量增加。高剂量的血清型特异性抗体的被动转移消除了病毒血症，但这些抗体的低剂量或交叉反应的多克隆或单克隆抗体在体内均增强了疾病，即使体外抗体水平具有中和作用。相比之下，一种不能结合 FcγR 的基因工程抗体变体 (E60-N297Q) 对 ADE 诱导的致死性挑战表现出预防和治疗功效。这些观察结果为抗体增强的登革热疾病的发病机制提供了深入了解，并确定了针对登革热的治疗性抗体设计的新策略。
