Potential immune-mediated genes expression induced by dengue antibodies enhance zika virus infection in THP-1 cell line

Abstract

Purpose: Dengue virus (DENV) and zika virus (ZIKV) belong to the same family of flaviviridae. Due to high homology of amino acid sequences between DENV and ZIKV (42.9%, 42.5% and 57.0% identical for capsid, prM and E regions, respectively), Anti-DENV antibodies (DENV Ab) routinely show cross-reactivity in serological assays with ZIKV. In this study, we report the ability of sub-neutralizing DENV Ab to enhance (ADE) the ability of three different strains of ZIKV (One African and two Asian genotypes, Thailand and Philippines) to infect THP-1 monocytes cells. The potential immune mediators underlying ADE mechanism were also demonstrated. Methods & Materials: Antibody dependent enhancement of ZIKV infection was tested using THP-1 cell line. Serial ten-fold dilution of pooled DENV infected sera or flavivirus negative human serum were separately mixed with each strains of ZIKV prior to infect THP-1 cells. Cells and supernatant were harvested to determined the level of intracellular ZIKV RNA and infectious virus production by quantitative RT-PCR (qRT-PCR) and plaque assay, respectively. The expression of immune-related genes including IRF-I, MDA5, RIG-I, ATG5, DAK, NOS2, SOCS3, IL-6 and IL-10 was evaluated by qRT-PCR using specific primer. Results: Although non-significant differences in intracellular viral RNA were observed, significantly higher infectious ZIKV production were found when incubated in the presence of sub-neutralizing DENV Ab. We further investigated the ability of DENV Ab to facilitate ZIKV cell entry. DENV Ab increased cell entry of all ZIKV strains tested. Using quantitative RT-PCR, we measured various immune cytokines and mediators that may have contributed to the DENV Ab enhancement of ZIKV infection (ZIKV-ADE). Up-regulation of IL-10 was observed in ZIKV-ADE as early as 12 h post infection, whereas expression of MDA-5 and IRF-1 was down-regulated in the presence of DENV Ab expression comparing to ZIKV infection alone. Conclusion: The results from this study illustrate potential immune mechanisms underlying DENV Ab enhancement of ZIKV-ADE, in vitro. This information is of particular relevance to DENV and ZIKV vaccine developments and in areas where both DENV and ZIKV are endemic.