Li Yiting, Liu Hongmei, Wu Yi, Zhang Xiaomei, Geng Juan, Wu Xin, Li Wengui, Zhang Zhenxing, Song Jianling, Zhang Yifang, Chai Jun
College of Veterinary Medicine, Yunnan Agricultural University, Kunming 650051, China.
Yunnan Tropical and Subtropical Animal Virus Disease Laboratory, Yunnan Animal Science and Veterinary Institute, Kunming 650224, China.
Viruses. 2025 Aug 5;17(8):1081. doi: 10.3390/v17081081.
Porcine circovirus type 2 (PCV2) is a globally prevalent swine pathogen that induces immunosuppression, predisposing pigs to subclinical infections. In intensive farming systems, PCV2 persistently impairs growth performance and vaccine efficacy, leading to substantial economic losses in the swine industry. Emerging evidence suggests that certain viruses exploit Suppressor of Cytokine Signaling 3 (SOCS3), a key immune checkpoint protein, to subvert host innate immunity by suppressing cytokine signaling. While SOCS3 has been implicated in various viral infections, its regulatory role in PCV2 replication remains undefined. This study aims to elucidate the mechanisms underlying the interplay between SOCS3 and PCV2 during viral pathogenesis. Porcine SOCS3 was amplified using RT-PCR and stably overexpressed in PK-15 cells through lentiviral delivery. Bioinformatics analysis facilitated the design of three siRNA candidates targeting SOCS3. We systematically investigated the effects of SOCS3 overexpression and knockdown on PCV2 replication kinetics and host antiviral responses by quantifying the viral DNA load and the mRNA levels of cytokines. PCV2 infection upregulated SOCS3 expression at both transcriptional and translational levels in PK-15 cells. Functional studies revealed that SOCS3 overexpression markedly enhanced viral replication, whereas its knockdown suppressed viral proliferation. Intriguingly, SOCS3-mediated immune modulation exhibited a divergent regulation of antiviral cytokines: PCV2-infected SOCS3-overexpressing cells showed elevated IFN-β but suppressed TNF-α expressions, whereas SOCS3 silencing conversely downregulated IFN-β while amplifying TNF-α responses. This study unveils a dual role of SOCS3 during subclinical porcine circovirus type 2 (PCV2) infection: it functions as a host-derived pro-viral factor that facilitates viral replication while simultaneously reshaping the cytokine milieu to suppress overt inflammatory responses. These findings provide novel insights into the mechanisms underlying PCV2 immune evasion and persistence and establish a theoretical framework for the development of host-targeted control strategies. Although our results identify SOCS3 as a key host determinant of PCV2 persistence, the precise molecular pathways involved require rigorous experimental validation.
猪圆环病毒2型（PCV2）是一种在全球范围内流行的猪病原体，可诱导免疫抑制，使猪易发生亚临床感染。在集约化养殖系统中，PCV2持续损害生长性能和疫苗效力，给养猪业造成巨大经济损失。新出现的证据表明，某些病毒利用细胞因子信号转导抑制因子3（SOCS3）（一种关键的免疫检查点蛋白）通过抑制细胞因子信号转导来颠覆宿主固有免疫。虽然SOCS3已被证明与多种病毒感染有关，但其在PCV2复制中的调节作用仍不明确。本研究旨在阐明病毒发病机制中SOCS3与PCV2相互作用的潜在机制。使用RT-PCR扩增猪SOCS3，并通过慢病毒递送在PK-15细胞中稳定过表达。生物信息学分析有助于设计三种靶向SOCS3的siRNA候选物。我们通过定量病毒DNA载量和细胞因子的mRNA水平，系统地研究了SOCS3过表达和敲低对PCV2复制动力学和宿主抗病毒反应的影响。PCV2感染在转录和翻译水平上均上调了PK-15细胞中SOCS3的表达。功能研究表明，SOCS3过表达显著增强病毒复制，而其敲低则抑制病毒增殖。有趣的是，SOCS3介导的免疫调节对抗病毒细胞因子表现出不同的调节作用：PCV2感染的SOCS3过表达细胞中IFN-β升高但TNF-α表达受到抑制，而SOCS3沉默则相反，下调IFN-β同时增强TNF-α反应。本研究揭示了SOCS3在亚临床猪圆环病毒2型（PCV2）感染过程中的双重作用：它作为一种宿主来源的促病毒因子，促进病毒复制，同时重塑细胞因子环境以抑制明显的炎症反应。这些发现为PCV2免疫逃逸和持续存在的潜在机制提供了新的见解，并为开发针对宿主的控制策略建立了理论框架。虽然我们的结果确定SOCS3是PCV2持续存在的关键宿主决定因素，但所涉及的精确分子途径需要严格的实验验证。
