Neuraminidase Augments Fc Receptor II-Mediated Antibody-Dependent Enhancement of Dengue Virus Infection

Abstract

Antibody-dependent enhancement (ADE) of dengue virus infection occurs when neutralizing antibodies at sub-neutralizing concentrations or non-neutralizing antibodies form complexes with the virus. These virus-antibody complexes can then attach to a Fc7 receptor-bearing cell, via the Fc portion of the immuno- globulin, resulting in an increased number of infected cells. ADE may be responsible in part for the most severe clinical manifestations of dengue virus infection which include haemorrhage and shock. Three classes of human Fcy receptors exist, FcTRI, FcTRII and FcTRIII. In this study, we examined the effects of neuraminidase on ADE of dengue virus infection mediated by the low- affinity FcTRII. K562 cells, which express only FcTRII, treated with neuraminidase resulted in augmentation of ADE of dengue virus infection by human anti-dengue antibodies. This augmented ADE of infection could be blocked by anti-FcTRII monoclonal antibody IV.3. Incubation of neuraminidase-treated K562 cells with IgG-coated human red blood cells resulted in an increase in the percentage of rosette formations compared with the untreated K562 cells. A bispecific antibody directed against FcTRII and dengue virus (IV. 3 × 2H2) enhanced virus infection. Neuraminidase also augmented ADE mediated by this antibody, but to a much lesser degree (by 50 %) compared with that seen using conventional human anti-dengue antibody (by 200 to 300%). Fluorescence-activated cell sorting analysis of neuraminidase-treated K562 ceils showed that the number of FcTRII-specific antibodies that bind to FcTRII increases by 15 to 20% after treatment with neuraminidase. These results indicate that neuraminidase augments ADE of dengue virus infection and that the augmented ADE is mediated through FcTRII.