Integrated multiomics reveals host-virus coadaptation in persistent foot-and-mouth disease virus infection

A comprehensive understanding of host-virus interactions during persistent foot-and-mouth disease virus (FMDV) infection is essential for elucidating the mechanisms that underpin disease causation by this highly contagious pathogen. This understanding necessitates the development of stable in vitro models. In this study, we established a model of persistent FMDV serotype O infection in Madin-Darby bovine kidney epithelial cells followed by integrated multiomics analyses. These analyses revealed that host cells adapt to persistent viral infection by reprogramming mitochondrial metabolism. This reprogramming is accompanied by alterations in mitochondrial structure and function, as well as the suppression of the apoptotic response in host cells. In particular, bystander cells, which are devoid of active viral replication, display enhanced proliferative capacity and possess a distinct microenvironmental signature that potentially increases viral susceptibility, facilitating sustained virus persistence within the cell population. Moreover, persistent viruses have evolved enhanced replicative fitness. Our findings elucidate the biological characteristics of FMDV-infected cell populations that persistently harbour the virus, reveal host-virus coadaptation, and highlight the critical role of bystander cells in sustaining persistent FMDV infection. These discoveries establish the foundation for further mechanistic studies of FMDV persistence maintenance.