Thulin Natalie K, Brewer R Camille, Sherwood Robert, Bournazos Stylianos, Edwards Karlie G, Ramadoss Nitya S, Taubenberger Jeffery K, Memoli Matthew, Gentles Andrew J, Jagannathan Prasanna, Zhang Sheng, Libraty Daniel H, Wang Taia T
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Proteomics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY 14853, USA.
Cell Rep. 2020 May 12;31(6):107642. doi: 10.1016/j.celrep.2020.107642.
Infant mortality from dengue disease is a devastating global health burden that could be minimized with the ability to identify susceptibility for severe disease prior to infection. Although most primary infant dengue infections are asymptomatic, maternally derived anti-dengue immunoglobulin G (IgGs) present during infection can trigger progression to severe disease through antibody-dependent enhancement mechanisms. Importantly, specific characteristics of maternal IgGs that herald progression to severe infant dengue are unknown. Here, we define ≥10% afucosylation of maternal anti-dengue IgGs as a risk factor for susceptibility of infants to symptomatic dengue infections. Mechanistic experiments show that afucosylation of anti-dengue IgGs promotes FcγRIIIa signaling during infection, in turn enhancing dengue virus replication in FcγRIIIa monocytes. These studies identify a post-translational modification of anti-dengue IgGs that correlates with risk for symptomatic infant dengue infections and define a mechanism by which afucosylated antibodies and FcγRIIIa enhance dengue infections.
登革热疾病导致的婴儿死亡是一项沉重的全球健康负担，若能在感染前识别出严重疾病的易感性，这一负担便可降至最低。尽管大多数婴儿初次感染登革热并无症状，但感染期间母体来源的抗登革热免疫球蛋白G（IgG）可通过抗体依赖增强机制促使病情发展为重症。重要的是，预示婴儿登革热发展为重症的母体IgG的具体特征尚不清楚。在此，我们将母体抗登革热IgG≥10%的去岩藻糖基化定义为婴儿易患症状性登革热感染的一个危险因素。机制实验表明，抗登革热IgG的去岩藻糖基化在感染期间促进FcγRIIIa信号传导，进而增强登革热病毒在FcγRIIIa单核细胞中的复制。这些研究确定了一种与婴儿症状性登革热感染风险相关的抗登革热IgG的翻译后修饰，并明确了去岩藻糖基化抗体和FcγRIIIa增强登革热感染的机制。
