Cheng Pengyuan, Wang Xiangwei, Wang Shasha, Ren Shanhui, Liang Zhengji, Guo Ke, Qu Min, Meng Xuelian, Dou Yongxi, Yin Xiangping, Sun Yuefeng
State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou University, Lanzhou, China.
J Virol. 2025 Feb 25;99(2):e0182724. doi: 10.1128/jvi.01827-24. Epub 2025 Jan 22.
Lumpy skin disease virus (LSDV) infection poses a significant threat to global cattle farming. Currently, effective therapeutic agents are lacking. TMP269, a small molecule inhibitor of class IIa histone deacetylase inhibitor, plays a vital role in cancer therapy. In this study, we demonstrated that TMP269 treatment inhibits the early-stage replication of LSDV in a dose-dependent manner. RNA sequencing data revealed that metabolism-related signaling pathways were significantly enriched after LSDV infection. Furthermore, untargeted metabolomics analysis revealed that lysophosphatidic acid (LPA), a key metabolite of the glycerophospholipid pathway, was upregulated following LSDV infection and downregulated after TMP269 treatment. In addition, exogenous LPA promotes LSDV replication by activating the mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinase (ERK) signaling pathway and suppressing the host's innate immune response. Furthermore, treatment with the LPA receptor inhibitor Ki16425 suppressed LSDV replication and promoted the host's innate immune response. These findings suggest that LSDV infection can induce LPA expression and aid viral activation of the MEK/ERK signaling pathway and escape of the host's innate immune response, whereas TMP269 treatment can inhibit LPA production and limit its promotion of LSDV replication. These data identified the antiviral mechanism of TMP269 and a novel mechanism by which LSDV inhibits host innate immune responses, providing insights into the development of new preventive or therapeutic strategies targeting altered metabolic pathways.IMPORTANCELumpy skin disease virus (LSDV) poses a significant threat to global cattle farming. Owing to insufficient research on LSDV infection, pathogenesis, and immune escape mechanisms, prevention and control methods against LSDV infection are lacking. Here, we found that TMP269, a class IIa histone deacetylase inhibitor, significantly inhibited LSDV replication. We further demonstrated that TMP269 altered LSDV infection-induced host glycerophospholipid metabolism. In addition, TMP269 decreased the accumulation of lysophosphatidic acid (LPA), a key metabolite in glycerophospholipid metabolism, induced by LSDV infection, and exogenous LPA-promoted LSDV replication by activating the mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinase (ERK) signaling pathway and suppressing the host innate immune response. Our findings identified the antiviral mechanism of TMP269 and a novel mechanism by which LSDV manipulates host signaling pathways to promote its replication, offering insights into the development of novel antiviral agents against LSDV infection.
结节性皮肤病病毒（LSDV）感染对全球养牛业构成重大威胁。目前，缺乏有效的治疗药物。TMP269是一种IIa类组蛋白去乙酰化酶抑制剂小分子，在癌症治疗中发挥着至关重要的作用。在本研究中，我们证明TMP269处理以剂量依赖性方式抑制LSDV的早期复制。RNA测序数据显示，LSDV感染后代谢相关信号通路显著富集。此外，非靶向代谢组学分析显示，甘油磷脂途径的关键代谢物溶血磷脂酸（LPA）在LSDV感染后上调，在TMP269处理后下调。此外，外源性LPA通过激活丝裂原活化蛋白激酶（MEK）/细胞外信号调节激酶（ERK）信号通路并抑制宿主的先天免疫反应来促进LSDV复制。此外，用LPA受体抑制剂Ki16425处理可抑制LSDV复制并促进宿主的先天免疫反应。这些发现表明，LSDV感染可诱导LPA表达，有助于病毒激活MEK/ERK信号通路并逃避宿主的先天免疫反应，而TMP269处理可抑制LPA产生并限制其对LSDV复制的促进作用。这些数据确定了TMP269的抗病毒机制以及LSDV抑制宿主先天免疫反应的新机制，为针对改变的代谢途径开发新的预防或治疗策略提供了见解。
重要性
结节性皮肤病病毒（LSDV）对全球养牛业构成重大威胁。由于对LSDV感染、发病机制及免疫逃逸机制的研究不足，缺乏针对LSDV感染的防控方法。在此，我们发现IIa类组蛋白去乙酰化酶抑制剂TMP269显著抑制LSDV复制。我们进一步证明TMP269改变了LSDV感染诱导的宿主甘油磷脂代谢。此外，TMP269减少了LSDV感染诱导的甘油磷脂代谢关键代谢物溶血磷脂酸（LPA）的积累，外源性LPA通过激活丝裂原活化蛋白激酶（MEK）/细胞外信号调节激酶（ERK）信号通路并抑制宿主先天免疫反应促进LSDV复制。我们的数据确定了TMP269的抗病毒机制以及LSDV操纵宿主信号通路以促进其复制的新机制，为开发针对LSDV感染的新型抗病毒药物提供了见解。
