Targeting of the cellular ATM rather than ATR kinase exhibits therapeutic potential during the lumpy skin disease virus infection in vivo and in vitro.

Due to the lack of timely vaccine prevention and effective drug treatment, lumpy skin disease is increasingly becoming a global epidemic, including in China. There is an urgent need to explore the pathogenic mechanism of lumpy skin disease virus (LSDV) and develop practical therapeutic approaches. The present study provides concrete evidence for the simultaneous induction and activation of nuclear ATM-mediated double-strand break and ATR kinase-dependent single-strand break signaling cascades during LSDV replication in the cytoplasm. Specific drug-inhibitory experiments targeting ATM and ATR kinase activity have showed that LSDV activates the host deoxyribonucleic acid (DNA) damage response (DDR) to facilitate viral replication via ATM-Chk2 rather than the ATR-Chk1 signaling axis in vitro. Meanwhile, animal experiments corroborated the efficacy of an inhibitor drug targeting ATM kinase in decreasing the clinical symptoms of LSDV-infected cattle in vivo. These findings highlight how LSDV exploits the nuclear DDR pathway to enhance replication in the cytoplasmic viral factory, deepening our understanding of virus-host interactions and providing a new target for developing specific antiviral drugs and interventions.