Arginine downstream metabolites spermidine and putrescine, but not spermine, contribute to PCV2 replication.

Porcine circovirus type 2 (PCV2), a major pathogen of PCV2-associated diseases, causes immense economic losses. Understanding the cellular metabolic reprogramming induced by viruses provides novel clues for screening antiviral drugs. However, until now, no reports have described the cellular metabolic profile during PCV2 infection. In this study, we performed untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis of PCV2-infected PK-15 cells, and found that PCV2 infection upregulated significantly arginine and its metabolite spermidine. Further, we found that arginine downstream metabolites spermidine and putrescine markedly promoted PCV2 replication and played a proviral role during the replication stage of PCV2 infection. Difluoromethylornithine (DFMO)-an ornithine decarboxylase 1 (ODC1) inhibitor-decreases endogenous polyamine levels, and its treatment suppressed PCV2 replication. Supplementation with exogenous spermidine or putrescine, but not spermine, strikingly facilitated PCV2 replication, and inhibition of polyamine biogenesis significantly curtailed PCV2 replication in vitro and in the murine model. Taken together, the study revealed that spermidine plays an important proviral role in PCV2 replication and suggests that cellular polyamine metabolism is a suitable target for therapeutic intervention against PCV2 infection.