Human FcγRIIIa activation on splenic macrophages drives the in vivo pathogenesis of dengue disease

Abstract

Although dengue virus (DENV) infection typically causes asymptomatic disease, DENV-infected patients can experience severe complications. A risk factor for symptomatic disease is pre-existing anti-DENV IgG antibodies. Cellular assays suggested that these antibodies can enhance viral infection of Fc{gamma} receptor (Fc{gamma}R)-expressing myeloid cells. Recent studies, however, revealed more complex interactions between anti-DENV antibodies and specific Fc{gamma}Rs by demonstrating that modulation of the IgG Fc glycan correlates with disease severity. To investigate the in vivo mechanisms of antibody-mediated dengue pathogenesis, we developed a mouse model for dengue disease that recapitulates the unique complexity of human Fc{gamma}Rs. Our studies reveal that the in vivo pathogenic activity of anti-DENV IgG antibodies is exclusively mediated through engagement of Fc{gamma}RIIIa expressed on splenic macrophages, resulting in inflammatory sequelae and mortality. These findings highlight the importance of IgG-Fc{gamma}RIIIa interactions in dengue disease, with important implications in the design of safer vaccination approaches and effective therapeutic strategies.