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. <i>C1QTNF6</i> 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 <i>C1QTNF6</i> in regulating PCV2 replication remains poorly characterized. Here, we analyzed <i>C1QTNF6</i> expression patterns and identified its highly specific expression in placental tissues in both humans and pigs. We then overexpressed <i>C1QTNF6</i> and conducted RNA sequencing analysis. Remarkably, 68 upregulated genes were identified, and most of them were interferon-stimulated genes (ISGs), including <i>MX2</i> and <i>ISG15</i>. 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 <i>C1qtnf6</i>, <i>MX2</i>, and <i>IFIT2</i>. Moreover, experimental data indicated that <i>C1QTNF6</i> inhibits PCV2 replication by targeting ISGs, while restoring <i>MX2</i> expression. To verify whether <i>C1QTNF6</i>-<i>MX2</i> antiviral axis mediates this antiviral effect, we constructed an <i>MX2</i> overexpression plasmid and demonstrated that <i>MX2</i> overexpression indeed significantly suppressed PCV2 replication. Together, these results provide important insights into PCV2-host interactions and the development of novel antiviral strategies.