Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China; Department of Pediatric Intensive Care Unit, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
Redox Biol. 2023 Sep;65:102837. doi: 10.1016/j.redox.2023.102837. Epub 2023 Aug 1.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV) and with a high fatality rate. Thrombocytopenia is a major clinical manifestation observed in SFTS patients, but the underlying mechanism remains largely unclear. Here, we explored the effects of SFTSV infection on platelet function in vivo in severely infected SFTSV IFNar mice and on mouse and human platelet function in vitro. Results showed that SFTSV-induced platelet clearance acceleration may be the main reason for thrombocytopenia. SFTSV-potentiated platelet activation and apoptosis were also observed in infected mice. Further investigation showed that SFTSV infection induced platelet reactive oxygen species (ROS) production and mitochondrial dysfunction. In vitro experiments revealed that administration of SFTSV or SFTSV glycoprotein (Gn) increased activation, apoptosis, ROS production, and mitochondrial dysfunction in separated mouse platelets, which could be effectively ameliorated by the application of antioxidants (NAC (N-acetyl-l-cysteine), SKQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) and resveratrol). In vivo experiments showed that the antioxidants partially rescued SFTSV infection-induced thrombocytopenia by improving excessive ROS production and mitochondrial dysfunction and down-regulating platelet apoptosis and activation. Furthermore, while SFTSV and Gn directly potentiated human platelet activation, it was completely abolished by antioxidants. This study revealed that SFTSV and Gn can directly trigger platelet activation and apoptosis in an ROS-MAPK-dependent manner, which may contribute to thrombocytopenia and hemorrhage during infection, but can be abolished by antioxidants.
严重发热伴血小板减少综合征（SFTS）是一种由 SFTS 病毒（SFTSV）引起的新兴蜱传传染病，死亡率较高。血小板减少是 SFTS 患者的主要临床表现，但发病机制尚不清楚。本研究旨在探讨 SFTSV 感染对严重感染 SFTSV IFNar 小鼠体内血小板功能以及对小鼠和人血小板体外功能的影响。结果表明，SFTSV 诱导的血小板清除加速可能是血小板减少的主要原因。在感染小鼠中还观察到 SFTSV 增强的血小板激活和凋亡。进一步研究表明，SFTSV 感染诱导血小板活性氧（ROS）产生和线粒体功能障碍。体外实验表明，SFTSV 或 SFTSV 糖蛋白（Gn）的给药增加了分离的小鼠血小板的激活、凋亡、ROS 产生和线粒体功能障碍，抗氧化剂（NAC（N-乙酰-L-半胱氨酸）、SKQ1（10-（6'-质体醌基）癸基三苯基膦）和白藜芦醇）的应用可有效改善这些变化。体内实验表明，抗氧化剂通过改善过度的 ROS 产生和线粒体功能障碍以及下调血小板凋亡和激活，部分挽救了 SFTSV 感染诱导的血小板减少症。此外，虽然 SFTSV 和 Gn 直接增强了人血小板的激活，但抗氧化剂完全消除了这种作用。本研究揭示了 SFTSV 和 Gn 可直接通过 ROS-MAPK 依赖性途径触发血小板激活和凋亡，这可能导致感染期间血小板减少和出血，但可被抗氧化剂所阻断。
