Kavli Affiliate: Charles Rice
| Authors: Rachel Yamin, Kevin S Kao, Margaret R MacDonald, Tineke Cantaert, Charles M Rice, Jeffrey V Ravetch and Stylianos Bournazos
| Summary:
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 Fcγ receptor (FcγR)-expressing myeloid cells. Recent studies, however, revealed more complex interactions between anti-DENV antibodies and specific FcγRs 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 FcγRs. Our studies reveal that the in vivo pathogenic activity of anti-DENV IgG antibodies is exclusively mediated through engagement of FcγRIIIa expressed on splenic macrophages, resulting in inflammatory sequelae and mortality. These findings highlight the importance of IgG-FcγRIIIa interactions in dengue disease, with important implications in the design of safer vaccination approaches and effective therapeutic strategies. Competing Interest Statement The authors have declared no competing interest.