Zika Virus Replication in a Mast Cell Model is Augmented by Dengue Virus Antibody-Dependent Enhancement and Features a Selective Immune Mediator Secretory Profile

Zika virus and dengue virus are evolutionarily related and structurally similar mosquito-borne Flaviviruses. These congruencies can lead to cross-reactive antibody binding, whereby antibodies generated from previous dengue virus immunity can augment Zika virus replication in vitro. This phenomenon, termed antibody-dependent enhancement, may participate in the clinical manifestations detected in areas with Flavivirus cocirculations where Zika virus is endemic; however, a causal relationship has yet to be determined. The KU812 mast cell/basophil line was integral in identifying the first Flavivirus infection in mast cells and serves as an effective in vitro model to study dengue virus antibody-dependent enhancement. Mast cells, sentinel white blood cells intrinsic in coordinating early immune defenses, are characteristically situated in the intradermal space and are therefore among the first immune cells interfaced with blood-feeding mosquitoes. Here, we tested whether KU812 cells were permissive to Zika virus, how previous dengue virus immunity might augment Zika virus infection, and whether either condition induces an immunological response. We report an antibody-dependent enhancement effect of Zika virus infection in KU812 cells across multiple time points (48, 72, and 96 hours postinfection [hpi]) and a range of multiplicities of infection (4.0 x 10(-3) to 4) using various concentrations of cross-reactive dengue virus monoclonal antibodies (D11C and 1.6D). This antigen-specific antibody-mediated infection was selectively coupled to chemokine ligand 5 (CCL5), interleukin 1 beta (IL-1 beta), and C-X-C motif chemokine ligand 10 (CXCL10) secretion and a reduction in granzyme B (GrB) release. Therefore, mast cells and/or basophils may significantly augment Zika virus infection in the context of preexisting dengue virus immunity. IMPORTANCE Antibodies generated against one dengue serotype can enhance infection of another by a phenomenon called antibody-dependent enhancement (ADE). Additionally, antigenic similarities between Zika and dengue viruses can promote Zika virus infection by way of ADE in vitro using these very same anti-dengue antibodies. We used the KU812 cell line to demonstrate for the first time that anti-dengue antibodies enhanced infectious Zika virus replication in a mast cell model and specifically increased CCL5, CXCL10, and IL-1 beta, while also impairing granzyme B secretion. Furthermore, enhanced Zika virus infection and selective mediator release were mechanistically dependent on fragment crystallizable gamma receptor II (Fc gamma RII). These findings establish a new model for Zika virus research and a new subcategory of immune cells previously unexplored in the context of Zika virus enhancement while being some of the very first immune cells likely to meet a blood-feeding infected mosquito.

Automated summary

This study demonstrates that anti-dengue antibodies can enhance Zika virus replication in mast cells and increase the secretion of CCL5, CXCL10, and IL-1β, while impairing granzyme B release. FcγRII is found to be mechanistically involved in the enhanced Zika virus infection and selective mediator release. These findings provide a new model for Zika virus research and explore a previously unexplored subcategory of immune cells in the context of Zika virus enhancement, which are among the first immune cells likely to encounter a blood-feeding infected mosquito.