Molecular Virology Laboratory, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, USA.
Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.
J Med Virol. 2024 Apr;96(4):e29522. doi: 10.1002/jmv.29522.
The tick-borne encephalitis virus (TBEV) serocomplex includes several medically important flavivirus members endemic to Europe, Asia, and North America, which can induce severe neuroinvasive or viscerotropic diseases with unclear mechanisms of pathogenesis. Langat virus (LGTV) shares a high sequence identity with TBEV but exhibits lower pathogenic potential in humans and serves as a model for virus-host interactions. In this study, we demonstrated that LGTV infection inhibits the activation of gp130/JAK/STAT (Janus kinases (JAK) and signal transducer and activator of transcription (STAT)) signaling, which plays a pivotal role in numerous biological processes. Our data show that the LGTV-infected cells had significantly lower phosphorylated STAT3 (pSTAT3) protein upon oncostatin M (OSM) stimulation than the mock-infected control. LGTV infection blocked the nuclear translocation of STAT3 without a significant effect on total STAT3 protein level. LGTV inhibited JAK1 activation and reduced gp130 protein expression in infected cells, with the viral NS5 protein mediating this effect. TBEV infection also reduces gp130 level. On the other hand, pretreatment of Vero cells with OSM significantly reduces LGTV replication, and STAT1/STAT2 knockdown had little effect on OSM-mediated antiviral effect, which suggests it is independent of STAT1/STAT2 and, instead, it is potentially mediated by STAT3 signlaing. These findings shed light on the LGTV and TBEV-cell interactions, offering insights for the future development of antiviral therapeutics and improved vaccines.
蜱传脑炎病毒（TBEV）血清群包括几种在欧洲、亚洲和北美洲流行的医学上重要的黄病毒属成员，它们可引起发病机制尚不清楚的严重神经侵袭性或内脏嗜性疾病。兰加特病毒（LGTV）与 TBEV 具有很高的序列同一性，但在人类中表现出较低的致病潜能，可作为病毒-宿主相互作用的模型。在本研究中，我们证明 LGTV 感染抑制了 gp130/JAK/STAT（Janus 激酶（JAK）和信号转导和转录激活因子（STAT））信号的激活，该信号在许多生物学过程中发挥着关键作用。我们的数据表明，与 mock 感染对照相比，在奥曲肽（OSM）刺激下，LGTV 感染的细胞中磷酸化 STAT3（pSTAT3）蛋白的水平显著降低。LGTV 感染阻止了 STAT3 的核转位，而对总 STAT3 蛋白水平没有显著影响。LGTV 抑制了感染细胞中 JAK1 的激活和 gp130 蛋白的表达，其病毒 NS5 蛋白介导了这种作用。TBEV 感染也降低了 gp130 水平。另一方面，用 OSM 预处理 Vero 细胞可显著降低 LGTV 的复制，而 STAT1/STAT2 的敲低对 OSM 介导的抗病毒作用几乎没有影响，这表明它独立于 STAT1/STAT2，而是可能通过 STAT3 信号介导。这些发现揭示了 LGTV 和 TBEV 与细胞的相互作用，为未来开发抗病毒治疗药物和改进疫苗提供了新的思路。
