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.