College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China.
College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China.
Vet Microbiol. 2021 Jul;258:109098. doi: 10.1016/j.vetmic.2021.109098. Epub 2021 May 4.
Porcine circovirus 2 (PCV2) has been proved to increase the risk of other pathogens infection via immunosuppression. Although the co-infection of PCV2 and porcine parvovirus (PPV) is commonly observed in worldwide, the relative immune mechanisms promoting PPV infection in PCV2-infected piglets are currently unknown. Herein, we found that PCV2 infection suppressed IFN-β expression and promoted PPV infection in the piglets. Consistent with this finding, we confirmed that PCV2 infection significantly inhibited the induction of IFN-β to promote PPV replication in cell level. Furthermore, PCV2 infection attenuated the K63-linked ubiquitination of STING induced by PPV, blocked the formation of complex of STING, TBK1 and IRF3, and further prevented the phosphorylation of TBK1 and IRF3, resulting in a decreased IFN-β transcription response to PPV infection. Consistently, using cGAMP to direct stimulate STING also appeared a reduced STING-K63 ubiquitination and IFN-β induction in PCV2-infected cells. However, we noted that knockdown of p38-MAPK signaling could markedly attenuate the inhibitory effect of PCV2 on STING-K63 ubiquitination, and improve the induction of IFN-β in PCV2-infected whenever theses cells were challenged with PPV infection or cGAMP stimulation. Meanwhile, we found that PCV2 infection promoted the phosphorylation of USP21 to inhibit the K63 ubiquitination of STING and the transcription of IFN-β via activation of p38-MAPK signaling. Taken together, our results demonstrate that PCV2 infection activates the p38-MAPK signaling pathway-mediated USP21 phosphorylation to inhibit the K63 ubiquitination of STING, which prevents the phosphorylation and transportation to the nucleus of IRF3, leading to an increase risk for PPV infection.
猪圆环病毒 2（PCV2）已被证实通过免疫抑制增加其他病原体感染的风险。虽然 PCV2 和猪细小病毒（PPV）的共同感染在全球范围内很常见，但目前尚不清楚促进 PCV2 感染仔猪中 PPV 感染的相对免疫机制。在这里，我们发现 PCV2 感染抑制 IFN-β 的表达并促进 PCV2 感染仔猪中的 PPV 感染。与这一发现一致，我们证实 PCV2 感染显著抑制 IFN-β 的诱导，从而促进细胞水平上的 PPV 复制。此外，PCV2 感染减弱了 PPV 诱导的 STING 的 K63 连接泛素化，阻断了 STING、TBK1 和 IRF3 复合物的形成，并进一步阻止了 TBK1 和 IRF3 的磷酸化，导致 IFN-β 对 PPV 感染的转录反应减少。一致地，使用 cGAMP 直接刺激 STING 也在 PCV2 感染的细胞中出现 STING-K63 泛素化和 IFN-β 诱导减少。然而，我们注意到，p38-MAPK 信号的敲低可显著减弱 PCV2 对 STING-K63 泛素化的抑制作用，并在这些细胞受到 PPV 感染或 cGAMP 刺激时改善 PCV2 感染后的 IFN-β 诱导。同时，我们发现 PCV2 感染促进 USP21 的磷酸化，通过激活 p38-MAPK 信号通路抑制 STING 的 K63 泛素化和 IFN-β 的转录。总之，我们的结果表明，PCV2 感染激活 p38-MAPK 信号通路介导的 USP21 磷酸化，抑制 STING 的 K63 泛素化，阻止 IRF3 的磷酸化和向核内运输，导致 PPV 感染风险增加。
