Involvement of the Fc gamma receptor IIA cytoplasmic domain in antibody-dependent enhancement of dengue virus infection.

Sub-neutralizing concentrations of antibody to dengue virus (DENV) enhance DENV infection of Fc gamma receptor-expressing cells. This phenomenon, referred to as antibody-dependent enhancement (ADE), has been hypothesized to be responsible for the severe form of DENV infection, including dengue haemorrhagic fever and dengue shock syndrome. To analyse further the mechanisms of ADE in vitro, this study introduced a series of cytoplasmic mutants into human Fc gammaRIIA. The mutated Fc gammaRIIA was then expressed on COS-7 cells to see whether these mutants could enhance DENV infection. Wild-type Fc gammaRIIA enhanced DENV infection, consistent with previous reports using Fc gammaR-positive monocytes. Disruption of the immune tyrosine activation motif (ITAM) in the cytoplasmic domain of Fc gammaRIIA or removing the sequences between the two ITAM regions eliminated ADE. These findings suggest that the specific structure of the Fc gammaRIIA cytoplasmic domain is essential for the ability of Fc gammaRIIA to mediate ADE.