IgG fucosylation predicts dengue severity
Secondary infections with dengue virus (DENV) can produce life-threatening symptoms, including thrombocytopenia and hemorrhagic disease, when preexisting DENV-reactive immunoglobulin G1 (IgG1) antibodies promote the infection of immune cells. Although severe dengue symptoms are associated with increased levels of afucosylated IgG1 glycoforms, it is unclear whether this is simply a result of the infection or if it is a preexisting phenomenon that can dictate susceptibility to this disease. Bournazos et al. studied the Fab and Fc structures of anti-DENV antibodies from patients before and after infection and with variable disease outcomes (see the Perspective by de Alwis and Ooi). They found that DENV infection induced specific increases in IgG1 afucosylation, and levels of afucosylated IgG1 could indeed predict dengue disease severity, making IgG1 fucosylation status a potentially useful prognostic tool for the treatment of dengue patients.
Science, abc7303, this issue p. 1102; see also abj0435, p. 1041
Although antiviral antibodies generally confer protective functions, antibodies against dengue virus (DENV) are associated with enhanced disease susceptibility. Antibodies can mediate DENV infection of leukocytes via Fcγ receptors, likely contributing to dengue disease pathogenesis. To determine if this mechanism accounts for variable disease severity, we examined Fab and Fc structures of anti-DENV antibodies from patients before and after infection and with variable disease outcomes. Neither antibody titers nor neutralizing activity correlated with disease severity in DENV-infected populations. Rather, DENV infection induced a specific increase in immunoglobulin G1 (IgG1) afucosylation, and the levels of afucosylated IgG1 were predictive of dengue disease severity. Thus, the IgG1 fucosylation status represents a robust prognostic tool for dengue disease, highlighting the key role of the Fc glycan structure in dengue pathogenesis.