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 immunoglobulin, 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 lowaffinity 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.

Human FcγRII Cytoplasmic Domains Differentially Influence Antibody-Mediated Dengue Virus Infection

“…First, we focused on K562 cells: a human erythroleukemia cell line that normally expresses a single type of FcgR (FcgRIIa) with an activating cytoplasmic ITAM motif (18,19). K562 cells are widely used to study ADE of flaviviruses in vitro (20,21). We used specific mAbs to block surface FcgRIIa and specific siRNA to knockdown FcgRIIa expression at the mRNA level in K562 cells.…”

Molecular mechanism of pathogenesis of dengue virus: Entry and fusion with target cell

“…Studies using electron microscopy have indicated that attachment is a temperature independent process that occurs at both 40~ as well as at 37~ whereas viral penetration proceeds only at 37~ The penetration can occur by membrane fusion in mosquito C6/36 cells or by receptor-mediated endocytosis in monocytes (Barth, 1992;Hase et al, 1989). In presence of subneutralizing amounts of antibody, Fc receptors also mediate attachment and uptake of dengue viruses into certain target cells such as monocytes and macrophages (Golins and Porterfield, 1985; Mady et al, 1993). This entry mechanism, termed as antibodydependent enhancement (ADE), may play a role in development of DHF and the Dengue Shock Syndrome (DSS) as the consequence of sequential infections with different dengue serotypes (reviewed by Halstead, 1988).…”

Transmission dynamics and epidemiology of dengue: insights from age–stratified sero–prevalence surveys

“…In general ADE is the phenomenon by which cross-reactive antibodies generated by prior exposure to a heterologous strain enhance replication of a second invading strain. In vitro studies have demonstrated such replication enhancement for a variety of viruses, including dengue Mady et al 1991), other £aviviruses (Peiris et al 1981;Porter¢eld 1986), and HIV (Robinson et al 1988;Takeda et al 1988).…”