The C1QTNF6–MX2 Antiviral Axis Inhibits Porcine Circovirus Type 2 Replication in Porcine Macrophages

Porcine circovirus type 2 (PCV2), a widely distributed immunosuppressive virus, causes substantial economic losses in the global swine industry. C1QTNF6 has emerged as a novel immunoregulatory factor attracting increasing research interest due to its dual roles in both pro-inflammatory and antiviral immune responses. However, the role of C1QTNF6 in regulating PCV2 replication remains poorly characterized. Here, we analyzed C1QTNF6 expression patterns and identified its highly specific expression in placental tissues in both humans and pigs. We then overexpressed C1QTNF6 and conducted RNA sequencing analysis. Remarkably, 68 upregulated genes were identified, and most of them were interferon-stimulated genes (ISGs), including MX2 and ISG15. Functional enrichment analysis revealed that these genes were primarily associated with defense response to viruses and antiviral innate immune response. Subsequently, experimental data show that PCV2 infection significantly suppressed inflammatory responses and markedly downregulated the expression of C1qtnf6, MX2, and IFIT2. Moreover, experimental data indicated that C1QTNF6 inhibits PCV2 replication by targeting ISGs, while restoring MX2 expression. To verify whether C1QTNF6-MX2 antiviral axis mediates this antiviral effect, we constructed an MX2 overexpression plasmid and demonstrated that MX2 overexpression indeed significantly suppressed PCV2 replication. Together, these results provide important insights into PCV2-host interactions and the development of novel antiviral strategies.