Li Huan, Xue Qinghong, Wan Yangli, Chen Yan, Zeng Wei, Wei Shaopeng, Zhang Yanming, Wang Jingyu, Qi Xuefeng
College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.
China Institute of Veterinary Drug Control, Beijing 100000, China.
J Virol. 2021 Mar 10;95(10). doi: 10.1128/JVI.02045-20. Epub 2021 Jan 27.
Peste des petits ruminants virus (PPRV) is an important pathogen that seriously influences the productivity of small ruminants worldwide. PPRV has evolved several mechanisms to evade IFN-I responses. We report that a novel microRNA in goat PBMCs, novel miR-3, was upregulated by PPRV to facilitate virus infection. Furthermore, PPRV V protein alone was sufficient to induce novel miR-3 expression, and NF-κB and p38 pathway may involved in the induction of novel miR-3 during PPRV infection. Importantly, we demonstrated that novel miR-3 was a potent negative regulator of IFN-α production by targeting IRAK1, which resulted in the enhancement of PPRV infection. In addition, we found that PPRV infection can activated ISGs through IFN independent and IRF3 dependent pathway. Moreover, our data revealed that novel miR-3 mediated regulation of IFN-α production may involve in the differential susceptibility between goat and sheep to PPRV. Taken together, our findings identified a new strategy taken by PPRV to escape IFN-I-mediated antiviral immune responses by engaging cellular microRNA and, thus, improve our understanding of its pathogenesis. Peste des petits ruminants virus (PPRV) induce in the hosts a transient but severe immunosuppression, which threatens both small livestock and endangered susceptible wildlife populations in many countries. Despite extensive research has been explored, the mechanism underlying PPRV immune system evasion remains elusive. Our data provided the first direct evidence that novel microRNA-3 (novel miR-3) feedback inhibits type I IFN signaling when goat PBMCs are infected with PPRV vaccine strain N75/1, thus promoting the infection. In this study, the target of novel miR-3, IRAK1, which are important for PPRV-induced type I IFN production, have also been found. Moreover, we identified NF-κB and p38 pathways may involve in novel miR-3 induction in response to PPRV infection. Taken together, our research has provided new insight into understanding the effects of miRNA on host-virus interactions, and revealed a potential therapeutic target for antiviral intervention.
小反刍兽疫病毒（PPRV）是一种严重影响全球小反刍动物生产力的重要病原体。PPRV已经进化出多种机制来逃避I型干扰素反应。我们报道，山羊外周血单核细胞中的一种新型微小RNA——新型miR-3，被PPRV上调以促进病毒感染。此外，单独的PPRV V蛋白就足以诱导新型miR-3表达，并且NF-κB和p38信号通路可能参与PPRV感染期间新型miR-3的诱导。重要的是，我们证明新型miR-3通过靶向IRAK1成为I型干扰素产生的有效负调节因子，这导致PPRV感染增强。此外，我们发现PPRV感染可通过不依赖干扰素和依赖IRF3的途径激活干扰素刺激基因。而且，我们的数据表明新型miR-3介导的I型干扰素产生调节可能与山羊和绵羊对PPRV的易感性差异有关。综上所述，我们的研究结果确定了PPRV通过利用细胞微小RNA逃避I型干扰素介导的抗病毒免疫反应的新策略，从而增进了我们对其发病机制的理解。小反刍兽疫病毒（PPRV）在宿主体内诱导短暂但严重的免疫抑制，这对许多国家的小型家畜和濒危易感野生动物种群都构成威胁。尽管已经进行了广泛的研究，但PPRV逃避免疫系统的机制仍然不清楚。我们的数据提供了首个直接证据，即当山羊外周血单核细胞感染PPRV疫苗株N75/1时，新型微小RNA-3（新型miR-3）通过反馈抑制I型干扰素信号传导，从而促进感染。在本研究中，还发现了新型miR-3的靶标IRAK-1，它对PPRV诱导的I型干扰素产生很重要。此外，我们确定NF-κB和p38信号通路可能参与PPRV感染时新型miR-3的诱导。综上所述，我们的研究为理解微小RNA对宿主-病毒相互作用的影响提供了新的见解，并揭示了抗病毒干预的潜在治疗靶点。
