Dengue Virus Structural Proteins Are Expressed on the Surface of DENV-Infected Cells and Are a Target for Antibody-Dependent Cellular Phagocytosis.

Abstract

Background: Dengue virus (DENV) is an arboviral pathogen found in >100 countries and a source of significant morbidity and mortality. While the mechanisms underpinning the pathophysiology of severe Dengue are incompletely understood, it has been hypothesized that antibodies directed against the DENV envelope (E) protein can facilitate antibody-dependent enhancement (ADE) of the infection, increasing the number of infected cells and the severity of disease in an exposed individual. Accordingly, there is interest in defining mechanisms for directly targeting DENV-infected cells for immunologic clearance, an approach that bypasses the risk of ADE.

Methods: We have previously demonstrated that antibodies specific to DENV nonstructural protein 1 (NS1) can opsonize and facilitate the phagocytic clearance of DENV-infected cells. However, it is currently unclear if other DENV antigens are expressed on the surface of infected cells and if these antigens can be targeted by antibody-dependent clearance mechanisms.

Results: In this study, we demonstrate that DENV structural proteins are expressed on the surface of DENV-infected cells and that these antigens can be opsonized by both DENV-immune sera and monoclonal antibodies. In addition, DENV E-specific antibodies can facilitate phagocytic uptake of material from DENV-infected cells, resulting in the target-cell membrane localizing to endosomes of the engulfing phagocyte. Notably, there was no selective enrichment of DENV genomic material in monocytes that had phagocytosed DENV-infected cell material compared with nonphagocytic monocytes.

Discussion: In their totality, these data reinforce the concept that DENV E-reactive antibodies have a multifaceted role in DENV immunity and pathogenesis beyond neutralization and/or infection enhancement.