A dominant role for FcgammaRII in antibody-enhanced dengue virus infection of human mast cells and associated CCL5 release

Abstract

Dengue virus is a major mosquito-borne human pathogen with four known serotypes. The presence of antidengue virus antibodies in the serum of individuals prior to dengue virus infection is believed to be an important risk factor for severe dengue virus disease as a result of the phenomenon of antibody-dependent enhancement operating on Fc receptor (FcR)-bearing cells. In addition to blood monocytes, mast cells are susceptible to antibody-enhanced dengue virus infection, producing a number of inflammatory mediators including IL-1, IL-6, and CCL5. Using the human mast cell-like lines KU812 and HMC-1 as well as primary cultures of human cord blood-derived mast cells (CBMC), we aimed to identify the participating FcRs in antibody-enhanced mast cell dengue virus infection, as FcRs represent a potential site for therapeutic intervention. CBMC expressed significant levels of FcgammaRI, FcgammaRII, and FcgammaRIII, and mast cell-like HMC-1 and KU812 cells expressed predominantly FcgammaRII. All four serotypes of dengue virus showed antibody-enhanced binding to KU812 cells. Specific FcgammaRII blockade with mAb IV.3 was found to significantly abrogate dengue virus binding to KU812 cells and CBMC in the presence of dengue-specific antibody. Dengue virus infection and the production of CCL5 by KU812 cells were also inhibited by FcgammaRII blockade.