Maternal Anti-Dengue IgG Fucosylation Predicts Susceptibility to Dengue Disease in Infants

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. [Display omitted] •Maternal anti-dengue afucosylation predicts symptomatic infections in infants•Afucosylated IgGs enhance dengue infections by promoting FcγRIIIa signaling•Dengue virus replication required calcineurin signaling network interactions Thulin et al. show that reduced fucosylation (afucosylation) of maternally derived anti-dengue IgGs is associated with symptomatic dengue infections in infants. Afucosylation of dengue immune complexes promotes FcγRIIIa signaling in monocytes, in turn enhancing infection through a post-entry pathway that is dependent on the calcineurin signaling network.