SummaryInfant 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. While most primary infant dengue infections are asymptomatic, maternally derived anti-dengue 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 biomarker for susceptibility of infants to symptomatic dengue infections. Mechanistic experiments show that anti-dengue afucosylation, a modification that enhances Fc affinity for the activating receptor FcγRIIIa, promotes infection of FcγRIIIa+ monocytes. FcγRIIIa signaling, in turn, enhances a post-entry step of dengue virus replication. These studies identify a biomarker that can be applied to reduce mortality associated with dengue viruses and define a mechanism by which afucosylated antibodies and FcγRIIIa enhance dengue infections.
Identification of a Broad-Spectrum Viral Inhibitor Targeting a Novel Allosteric Site in the RNA-Dependent RNA Polymerases of Dengue Virus and Norovirus
