Zhang Minmin, Shi Yujie, Lu Xinyin, Zhang Qiwei, Zhao Yubo, Li Shaohan, Wen Zhiyuan, Ge Jinying, Wang Xijun, Li Jie, Bu Zhigao, Yin Xin
State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
Jinyu Biotechnology Co., LTD, Hohhot, China.
PLoS Pathog. 2025 Jul 23;21(7):e1013362. doi: 10.1371/journal.ppat.1013362. eCollection 2025 Jul.
Lumpy skin disease virus (LSDV), a member of the genus Capripoxvirus within the family Poxviridae, causes significant disease in cattle and is classified as a notifiable disease by the World Organization for Animal Health (WOAH). The virus contains a double-stranded linear DNA genome of approximately 151 kbp, encoding 156 predicted open reading frames (ORFs) for various proteins. However, only a limited number of these proteins have been characterized, with the functions of many-particularly those encoded within the inverted terminal repeat (ITR) regions-remaining largely unknown. In this study, we utilized homologous recombination to generate LSDV mutants with deletions of the LSDV 001/156 gene to investigate its role. LSDV 001/156, an uncharacterized protein located within the ITR region, was identified as a late-expressed gene product incorporated into virions and involved in viral replication. Further analysis revealed that LSDV 001/156 acts as a negative regulator of the interferon (IFN) signaling pathway. It interacts with interferon regulatory factor 3 (IRF3), disrupting its dimerization and nuclear translocation, thereby attenuating IFN production. Functional studies demonstrated that the LSDV mutant lacking the 001/156 gene exhibited reduced replication and virulence in cattle compared to the wild-type virus, likely due to enhanced IFN responses in the absence of this immune-evasive protein. In summary, our findings uncover a novel role of the LSDV 001/156 gene in modulating the host intrinsic antiviral response, shedding light on the mechanisms underlying LSDV pathogenesis. This study highlights the importance of ITR-encoded genes in immune evasion and virulence, providing new insights into LSDV biology and its interactions with the host immune system.
结节性皮肤病病毒（LSDV）是痘病毒科山羊痘病毒属的成员，可在牛群中引发严重疾病，被世界动物卫生组织（WOAH）列为须通报的疾病。该病毒含有一个约151 kbp的双链线性DNA基因组，编码156个预测的开放阅读框（ORF）用于各种蛋白质。然而，这些蛋白质中只有少数已被鉴定，许多蛋白质的功能——特别是那些在反向末端重复（ITR）区域编码的蛋白质——在很大程度上仍然未知。在本研究中，我们利用同源重组技术构建了缺失LSDV 001/156基因的LSDV突变体，以研究其作用。LSDV 001/156是一种位于ITR区域的未鉴定蛋白质，被确定为一种晚期表达的基因产物，可整合到病毒粒子中并参与病毒复制。进一步分析表明，LSDV 001/156作为干扰素（IFN）信号通路的负调节因子。它与干扰素调节因子3（IRF3）相互作用，破坏其二聚化和核转位，从而减弱IFN的产生。功能研究表明，与野生型病毒相比，缺乏001/156基因的LSDV突变体在牛体内的复制和毒力降低，这可能是由于在缺乏这种免疫逃避蛋白的情况下IFN反应增强所致。总之，我们的研究结果揭示了LSDV 001/156基因在调节宿主固有抗病毒反应中的新作用，为LSDV发病机制提供了新的见解。本研究强调了ITR编码基因在免疫逃避和毒力方面的重要性，为LSDV生物学及其与宿主免疫系统的相互作用提供了新的认识。
