Mast Cell Infection by Zika Virus and Augmentation by Pre‐existing Dengue Virus Immunity
Authors: Coish Jeremia M. , Crozier Robert W.E. , Schieffelin John S. , Coorssen Jens R. , Hunter Fiona F. , MacNeil Adam J. 
Published: April 2020

As Brazil was preparing to host the 2016 Summer Olympic Games, they were also experiencing a Zika virus (ZIKV) epidemic coinciding with rising cases of microcephaly, a congenital disorder that causes severe lifelong neurological impairment. ZIKV was later confirmed as the first sexually transmitted teratogenic Flavivirus. During the epidemic, ZIKV cases were being diagnosed as mild forms of Dengue virus (DENV), another mosquito‐borne Flavivirus known for causing Dengue hemorrhagic fever (DHF). DHF 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 structural similarities between ZIKV and DENV surface proteins, emerging evidence suggests anti‐DENV antibodies can cross‐react with ZIKV at non‐neutralizing levels characteristic of ADE. Therefore, a pre‐existing DENV immunity may enhance ZIKV infection and could explain the severe ZIKV manifestations in Brazil. Sentinel cells positioned in the periphery that detect infection are integral in coordinating early immune defenses. Among these immune cells, the mast cell (MC) is uniquely positioned in the intradermal space, the first point of contact between the host and an infected mosquito. MC responses to virus can be modelled in vitro, including via use of the well‐characterized KU812 cell line which express surface proteins that may be exploited by ZIKV and DENV. In particular, Fcγ receptors (FcγR), which can bind to anti‐DENV IgG antibodies that cross‐react with ZIKV can facilitate ADE. However, to our knowledge this mechanism has never been explored in the context of ZIKV‐MC interactions. Here, we sought to determine if the FcγR‐bearing KU812 MC is susceptible to (1) direct ZIKV infection and (2) ZIKV infection in the presence of anti‐DENV antibodies that cross‐react with ZIKV. Cells were infected with PRVABC59‐ZIKV (MOI=1) directly or in the presence of anti‐DENV antibodies for 72 hours. Supernatants of ZIKV infected MC cultures were then harvested and virus titre quantified by plaque assay. A significant increase in viral titre (104 PFU/mL) was detected in MCs directly infected with ZIKV compared to MCs infected with UV‐inactivated ZIKV (0 PFU/mL). Furthermore, a significant viral titre (106 PFU/mL) was detected in MCs infected with ZIKV pre‐incubated with anti‐DENV antibodies when compared to MCs infected with ZIKV pre‐incubated with isotype control antibodies (104 PFU/mL). Additionally, significant CCL5 secretion was detected by ELISA in MCs infected in the presence of DENV antibodies compared to MCs directly infected with ZIKV, suggesting a distinct chemokine response to infection in each context. This work is the first to define ZIKV infection in a mast cell model. Additionally, we report an antigen‐specific antibody‐mediated infection of ZIKV in KU812 MCs. Therefore, MCs may be a contributor in ZIKV pathogenesis during a primary exposure and significantly augment ZIKV infection in the context of pre‐existing DENV immunity.Support or Funding InformationSupported by the Natural Sciences and Engineering Research council of Canada (NSERC); Canada Foundation for innovation (CFI); Government of Ontario; and, Brock University