Characterizing Zika and West Nile virus infection in mast cells and the antibody-dependent enhancement potential mediated by dengue virus antibodies

In the dermis, long-lived resident mast cells are well-situated to respond to mosquito-borne pathogens. Within the Flavivirus genus, dengue virus (DENV), Zika virus (ZIKV), and West Nile virus (WNV) are evolutionarily related mosquito-borne viruses with antigenic similarities. The antigenic similarities present between 4 circulating DENV serotypes create an immunological paradox called antibody-dependent enhancement (ADE) whereby previously generated DENV antibodies can augment a heterotypic DENV infection. Although antibodies are typically recognized as correlates for immunity, this idiosyncrasy is mechanistically mediated through FcγR-antibody interactions responsible for pathogen neutralization. Human DENV monoclonal antibodies (HmAbs) (1.6D and D11C) isolated from 2 different individuals have been characterized as neutralizing towards all DENV serotypes yet enhancing at sub-neutralizing concentrations in vitro. However, there is no data to suggest DENV antibodies facilitate WNV infection and whether mast cells are permissive to ZIKV or WNV in any context remains unexplored. Here we used KU812 cells to expand the resolution in which we understand viral-host interactions in the context of ZIKV and WNV infection. Both D11C and 1.6D HmAbs augmented ZIKV 72 hours post-infection (hpi). Across time (4, 48, 72, and 96 hpi), ADE of ZIKV by D11C was coupled to CCL5, IL-1b, and CXCL10 mediator release. Surface FcγRII was essential for both ZIKV and WNV ADE in mast cells since blocking the receptor-antigen interaction diminished both viral replication and immune mediator release. KU812 cells were exceptionally permissive to WNV infection (106-108 pfu/ml) across multiple timepoints (24, 48, and 72 hpi) independent of an ADE mechanism, although DENV HmAbs significantly augmented WNV replication kinetics. Increases in TNF, IL-1b, CCL5, CCL4, CCL3, CXCL8, CXCL10 were detected in cell-free supernatants 72 hpi for both canonical and ADE replication pathways, albeit ADE significantly increased mediator secretion kinetics as early as 48 hpi. This is the first work characterizing ZIKV infection in a mast cell model and illustrates FcγRII as the mechanistic contributor to ADE. Furthermore, this is the first time WNV infection has been described in a mast cell model and the first report of WNV ADE by DENV antibodies in any cell model.

Name thesis:degree_name

Ph.D. Applied Health Sciences

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Faculty of Applied Health Sciences

Department dc:contributor.department

Applied Health Sciences Program

Grantor

Brock University

Year dc:date.issued

2025

Author dc:creator

• Coish, Jeremia

Advisor dc:contributor.advisor

• MacNeil, Adam

• NATURAL SCIENCES::Biology::Cell and molecular biology::Immunology
• MEDICINE::Microbiology, immunology, infectious diseases::Microbiology::Virology

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/10464/19120

OAI identifier oai:identifier

oai:brocku.scholaris.ca:10464/19120