Early classical swine fever virus persistence is associated with cytotoxic and immunoregulatory transcriptional signatures distinct from protective C-strain vaccination.

Persistent classical swine fever virus (CSFV) infection represents a major challenge for disease control because persistently infected pigs remain clinically healthy while continuously shedding virus. However, the early immunological events associated with the establishment of viral persistence remain incompletely understood and require further investigation. In this study, we compared the peripheral blood mononuclear cell (PBMC) transcriptomes of neonatal piglets infected with the moderately virulent Catalonia01 CSFV strain, previously shown to induce postnatal persistent infection, with those of piglets vaccinated with the live attenuated C-strain vaccine. Samples were collected at 7 days post-infection or vaccination, before the onset of clinical signs or detectable anti-CSFV antibodies. Catalonia01-infected piglets exhibited high viral RNA loads and increased serum IFN-α levels, accompanied by enrichment of JAK-STAT and cytokine signaling pathways, indicating robust early innate antiviral activation. Transcriptomic analysis also revealed a marked cytotoxic transcriptional signature together with increased expression of immunoregulatory genes and lower expression of genes associated with MHC class II-mediated antigen presentation relative to C-strain-vaccinated animals. Together, these findings indicate that the early establishment of persistent infection occurs despite a robust antiviral transcriptional response, suggesting that immune activation alone is insufficient to achieve effective viral control. Collectively, these findings reveal distinct early transcriptional programs associated with Catalonia01 infection and protective C-strain vaccination, with persistent infection characterized by concurrent antiviral activation and immunoregulatory transcriptional signatures, further supporting and expanding the emerging concept of complex immune regulation during CSFV persistence.