NHC Key Laboratory of Biosafety, NHC Key Laboratory of Medical Virology and Viral Diseases, Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
J Med Virol. 2024 May;96(5):e29678. doi: 10.1002/jmv.29678.
Death due to severe influenza is usually a fatal complication of a dysregulated immune response more than the acute virulence of an infectious agent. Although spleen tyrosine kinase (SYK) as a critical immune signaling molecule and therapeutic target plays roles in airway inflammation and acute lung injury, the role of SYK in influenza virus infection is not clear. Here, we investigated the antiviral and anti-inflammatory effects of SYK inhibitor R406 on influenza infection through a coculture model of human alveolar epithelial (A549) and macrophage (THP-1) cell lines and mouse model. The results showed that R406 treatment increased the viability of A549 and decreased the pathogenicity and mortality of lethal influenza virus in mice with influenza A infection, decreased levels of intracellular signaling molecules under the condition of inflammation during influenza virus infection. Combination therapy with oseltamivir further ameliorated histopathological damage in the lungs of mice and further delayed the initial time to death compared with R406 treatment alone. This study demonstrated that phosphorylation of SYK is involved in the pathogenesis of influenza, and R406 has antiviral and anti-inflammatory effects on the treatment of the disease, which may be realized through multiple pathways, including the already reported SYK/STAT/IFNs-mediated antiviral pathway, as well as TNF-α/SYK- and SYK/Akt-based immunomodulation pathway.
死亡由于严重的流感通常是一个失调的免疫反应比急性毒力的传染性更强的一个致命的并发症。虽然脾酪氨酸激酶(SYK)作为一个关键的免疫信号分子和治疗靶点在气道炎症和急性肺损伤中发挥作用,SYK 在流感病毒感染中的作用尚不清楚。在这里,我们通过人肺泡上皮(A549)和巨噬细胞(THP-1)细胞系的共培养模型和小鼠模型研究了 SYK 抑制剂 R406 对流感感染的抗病毒和抗炎作用。结果表明,R406 处理增加了 A549 的活力,并降低了流感病毒感染小鼠的致病性和死亡率,降低了流感病毒感染时炎症条件下细胞内信号分子的水平。与单独使用 R406 治疗相比,奥司他韦联合治疗进一步改善了流感感染小鼠肺部的组织病理学损伤,并进一步延迟了首次死亡时间。本研究表明,SYK 的磷酸化参与了流感的发病机制,R406 对该疾病具有抗病毒和抗炎作用,这可能通过多种途径实现,包括已经报道的 SYK/STAT/IFNs 介导的抗病毒途径,以及 TNF-α/SYK-和 SYK/Akt 为基础的免疫调节途径。