# Opposing fates: a bipolar cellular model for FMDV replication shaped by 12C6+heavy-ion mutagenesis

## TL;DR

A new cell model for FMDV replication was created using heavy-ion mutagenesis, revealing two distinct cellular responses that either fight or support the virus.

## Contribution

The novel use of 12C6+ heavy-ion mutagenesis to generate a polarized cell model for studying FMDV replication.

## Key findings

- BHK-5 cells show a pre-activated antiviral state via RIG-I/TLR signaling and autophagy.
- BHK-7 cells enhance glycolysis and hijack the cell cycle to support viral replication.
- Transcription factor circuits, especially Runt and C2H2 zinc-finger families, drive these divergent responses.

## Abstract

By pioneering the use of an 80 MeV/u 12C6+ heavy-ion beam for mutagenesis, we have engineered a stably polarized BHK-21 cell model for FMDV replication.

This approach yielded two distinct clones: a highly antiviral line (BHK-5) and a highly proviral line (BHK-7). Multi-omics analyses were employed to investigate the mechanisms driving these divergent phenotypes.

The divergent phenotypes stem from a profound reprogramming of host transcriptional networks. The antiviral BHK-5 clone exhibits a pre-activated innate immune state, leveraging RIG-I/TLR signaling for a rapid interferon response and viral clearance via autophagy. In stark contrast, the proviral BHK-7 clone enhances glycolysis and activates the PI3K-Akt pathway to suppress TNF-mediated immunity and hijack the G2/M cell cycle phase, forming organized "virus factories." At the core of this reprogramming lies a systemic remodeling of transcription factor circuits, particularly within the Runt and C2H2 zinc-finger families.

Our work demonstrates that 12C6+ heavy-ion mutagenesis can rewire the host immunity-metabolism-cell cycle axis to dictate infection outcomes, providing a powerful framework and cellular toolkit for developing high-yield vaccine substrates and novel antiviral strategies.