Zika Virus Infection of Mast Cells is Not Associated with a Degranulation Response

Abstract Dengue virus (DENV) infection is augmented by a process called antibody-dependent enhancement (ADE), in which pre-existing DENV immunity can render an individual more susceptible to a subsequent DENV exposure. Based on Zika virus (ZIKV) and DENV structural similarities, emerging evidence suggests anti-DENV antibodies can cross-react with ZIKV at non-neutralizing levels characteristic of ADE. Mast cells (MC), sentinel white blood cells integral in coordinating early immune defences, have been identified as a principle contributor to DENV vascular leakage. This clinical manifestation is attributed to significant histamine release caused by MC degranulation, a characteristic MC activation response. However, to our knowledge ZIKV-MC interactions remain unexplored. MC responses to virus can be modelled in vitro, including via use of the well-characterized KU812 cell line which express Fcγ receptors. Here, we sought to determine if the KU812 MC is susceptible to (1) direct ZIKV infection; and (2) ADE in the presence of anti-DENV antibodies that cross-react with ZIKV. A significant increase in viral titre (104 PFU/mL) was detected, by plaque assay, in MC directly infected with ZIKV compared to MC infected with UV-inactivated ZIKV (0 PFU/mL). Furthermore, a significant viral titre (106 PFU/mL) was detected in MC infected with ZIKV pre-incubated with anti-DENV antibodies when compared to MC infected with ZIKV pre-incubated with isotype control antibodies (104 PFU/mL). Furthermore, unlike DENV induced degranulation of MC, ZIKV did not activate a degranulation response in this model or in a primary murine model. Therefore, MC may be a contributor in ZIKV pathogenesis without the classical degranulation response seen in DENV infected MC.