Abstract
Activating Fc gamma receptors (FcγRs) in hematopoietic cells serve to remove antibody-opsonized antigens, including dengue virus (DENV), from systemic circulation. While neutralizing antibody concentrations provide humoral immunity, cross-reactive or sub-neutralizing levels of antibody can result in antibody-dependent enhancement of DENV infection that increases overall viral burden. Recently, it has been suggested that the antibody levels needed for DENV neutralization differs when different FcγR is engaged. If this is true, the threshold titer used to infer immunity should be influenced by FcγR usage. Here, using cells that express both activating and inhibitory FcγRs, we show that the type of FcγR engaged during phagocytosis can influence the antibody concentration requirement for DENV neutralization. We demonstrate that phagocytosis through FcγRI requires significantly less antibody for complete DENV neutralization compared to FcγRIIA. Furthermore, when DENV is opsonized with sub-neutralizing levels of antibody, FcγRI-mediated phagocytosis resulted in significantly reduced DENV titers compared to FcγRIIA. However, while FcγRI may remove antibody-opsonized DENV more efficiently, this receptor is only preferentially engaged by clustering when neutralizing, but not sub-neutralizing antibody concentrations, were used. Collectively, our study demonstrates that activating FcγR usage may influence antibody titers needed for DENV neutralization.
Highlights
Dengue is the most common mosquito-borne viral disease globally
These findings suggest the h3H5 concentration required for complete dengue virus (DENV) neutralization in K562 coincides with that which aggregates DENV to co-ligate FccRIIB that inhibits phagocytosis, a mechanism that we demonstrated recently [18]
That complete DENV neutralization in K562 coincided with FccRIIB-mediated inhibition of phagocytosis raises the possibility that an even greater amount of antibody is needed to neutralize DENV if phagocytized by FccRIIA
Summary
Dengue is the most common mosquito-borne viral disease globally. It is caused by a positive-strand RNA virus, which exists as four antigenically distinct serotypes. Cross-reactive or sub-neutralizing levels of antibodies offer DENV with an alternative pathway of entry into monocytes, macrophages and dendritic cells through the activating Fc gamma receptors (FccRs) This pathway of infection, termed antibody-dependent enhancement of DENV infection (ADE), is hypothesized to be an important mechanism in the pathogenesis of severe dengue [3,4,5,6,7]. FccRs are broadly expressed by cells of hematopoietic origin and is composed of activating (FccRI, FccRIIA, and FccRIIIA) and inhibitory (FccRIIB) receptors [8] While these receptors could contribute to ADE [9,10], they are important in the removal of DENV opsonized with neutralizing levels of antibody. Delineating the determinants of neutralization or ADE upon FccR-mediated phagocytosis would be important for the understanding of immunity and pathogenesis, respectively, which could prove useful in refining vaccine development to overcome the currently observed limited immunity with the leading dengue vaccine candidate [11]
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