Yang Yu-Lin, Jia Huai-Jie, Sun Meng-Yao, Guo Ai-Min, Xia Tian, Shu Hong-Bing, Cao Li-Bo
State Key Laboratory for Animal Disease Control and Prevention, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences; College of Veterinary Medicine, Lanzhou University; Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China.
Department of Infectious Diseases, Medical Research Institute, Taikang Center for Life and Medical Sciences, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
mBio. 2025 Aug 25:e0167725. doi: 10.1128/mbio.01677-25.
Lumpy skin disease (LSD) is an emerging transboundary viral disease of livestock caused by the lumpy skin disease virus (LSDV), which has caused substantial economic losses and negatively impacted veterinary public health. The underlying pathogenic mechanisms remain poorly understood, limiting the effective prevention and control of LSD. Here, we identify LSDV-encoded protein LSDV001 as a positive regulator of IL-1β- and TNFα-triggered signaling. LSDV001 interacts with TAK1 and TAB2/3 and promotes assembly of the TAK1-TAB2/3 complex. This leads to IKK-dependent activation of the transcription factor NF-κB and induction of downstream inflammatory cytokines. LSDV001-deficient virus (LSDVΔ001) has attenuated the ability to activate NF-κB and induce the expression of inflammatory cytokines. Infection with LSDVΔ001 leads to smaller skin nodules and reduced inflammation compared to wild-type LSDV. Our findings suggest that LSDV001 acts as a key virulence factor of LSDV by promoting excessive inflammatory response upon infection.
Lumpy skin disease is a current global concern caused by the lumpy skin disease virus (LSDV), for which there is a lack of safe and efficient vaccines. In this study, we report that LSDV001 protein potentiates IL-1β- and TNFα-triggered IKK-dependent activation of NF-κB and transcription of inflammatory cytokines. Mechanistically, LSDV001 enhances inflammatory response by interacting with TAK1 and TAB2/3 to promote TAK1-TAB2/3 complex formation. We further demonstrate that LSDV001 deficiency attenuates LSDV-triggered inflammatory response and pathogenesis. Our findings identify a new virulence factor and reveal a novel pathogenic mechanism of LSDV by which LSDV001 enhances inflammatory response.
结节性皮肤病（LSD）是由结节性皮肤病病毒（LSDV）引起的一种新出现的家畜跨界病毒性疾病，已造成重大经济损失并对兽医公共卫生产生负面影响。其潜在的致病机制仍知之甚少，限制了对LSD的有效预防和控制。在此，我们确定LSDV编码的蛋白LSDV001是IL-1β和TNFα触发信号的正调节因子。LSDV001与TAK1和TAB2/3相互作用，并促进TAK1-TAB2/3复合物的组装。这导致转录因子NF-κB的IKK依赖性激活并诱导下游炎性细胞因子。缺乏LSDV001的病毒（LSDVΔ001）激活NF-κB和诱导炎性细胞因子表达的能力减弱。与野生型LSDV相比，感染LSDVΔ001导致皮肤结节更小且炎症减轻。我们的研究结果表明，LSDV001通过在感染时促进过度炎症反应而作为LSDV的关键毒力因子。
结节性皮肤病是由结节性皮肤病病毒（LSDV）引起的当前全球关注的问题，目前缺乏安全有效的疫苗。在本研究中，我们报告LSDV001蛋白增强IL-1β和TNFα触发的IKK依赖性NF-κB激活和炎性细胞因子的转录。机制上，LSDV001通过与TAK1和TAB2/3相互作用以促进TAK1-TAB2/3复合物形成来增强炎症反应。我们进一步证明LSDV001缺陷减弱了LSDV触发的炎症反应和发病机制。我们的研究结果确定了一种新的毒力因子，并揭示了LSDV通过LSDV001增强炎症反应的新致病机制。
