. doi: 10.1016/j.virs.2025.04.008
Citation: Hui Zhang, Ziyang Jiang, Haidang Liao, Jiang Li, Manli Wang, Yiwu Zhou, Zhihong Hu, Jia Liu. A mouse model of Crimean-Congo hemorrhagic fever virus-induced coagulopathy .VIROLOGICA SINICA, 2025, 40(3) : 499-502.  http://dx.doi.org/10.1016/j.virs.2025.04.008

一种克里米亚-刚果出血热病毒感染致凝血障碍的小鼠模型

  • 克里米亚-刚果出血热(CCHF)是由CCHFV引起的一种烈性传染病,被世界卫生组织列为需重点防控疾病,其典型特征包括高热、出血和多器官衰竭,病死率高达30%。凝血功能障碍是CCHF患者死亡的主要原因之一,但目前缺乏能够准确模拟人类凝血障碍的动物模型,严重制约了相关发病机制研究和药物开发。本研究利用STAT1基因敲除小鼠成功构建了CCHFV感染致凝血障碍的小鼠模型。通过高剂量CCHFV感染,小鼠表现出显著的体重下降及100%死亡率,并伴随血小板减少、淋巴细胞减少及肝酶(ALT/AST)水平升高,模拟了人类重症CCHF的临床特征。凝血功能检测显示,感染小鼠的尾部出血时间显著延长,凝血酶原时间(PT)和活化部分凝血活酶时间(APTT)缩短,而优球蛋白溶解时间(ELT)延长,提示凝血-纤溶系统失衡。病理分析进一步证实了肝脏和脾脏的血栓形成及肠道出血性病变。病毒载量检测表明CCHFV在脾脏和肝脏中高效复制。该模型首次在小鼠中重现了CCHFV感染相关的凝血障碍表型,为研究其致病机制及治疗策略提供了重要工具。

A mouse model of Crimean-Congo hemorrhagic fever virus-induced coagulopathy

  • Highlights
    1. A mouse model for CCHFV-induced coagulopathy was developed and characterized using STAT1 knockout mice.
    2. High doses of CCHFV resulted in delayed tail bleeding time, shortened PT and APTT, and prolonged ELT.
    3. Histopathology showed thrombus formation in the liver and the spleen as well as intestinal hemorrhages.

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    1. Bente, D.A., Alimonti, J.B., Shieh, W.J., Camus, G., Stroher, U., Zaki, S.,Jones, S.M., 2010. Pathogenesis and immune response of Crimean-Congo hemorrhagic fever virus in a STAT-1 knockout mouse model. J Virol, 84, 11089-11100.

    2. Bozkurt, I.,Esen, S., 2021. Association Between Severity Grading Score And Acute Phase Reactants In Patients With Crimean Congo Hemorrhagic Fever. Pathog Glob Health, 115, 496-498.

    3. Frank, M.G., Weaver, G.,Raabe, V., 2024. Crimean-Congo Hemorrhagic Fever Virus for Clinicians-Epidemiology, Clinical Manifestations, and Prevention. Emerg Infect Dis, 30, 854-863.

    4. Guo, R., Shen, S., Zhang, Y., Shi, J., Su, Z., Liu, D., Liu, J., Yang, J., Wang, Q., Hu, Z., Zhang, Y.,Deng, F., 2017. A new strain of Crimean-Congo hemorrhagic fever virus isolated from Xinjiang, China. Virol Sin, 32, 80-88.

    5. Hasanoglu, I., Guner, R., Carhan, A., Kocak Tufan, Z., Yagci-Caglayik, D., Guven, T., Yilmaz, G.R.,Tasyaran, M.A., 2016. Crucial parameter of the outcome in Crimean Congo hemorrhagic fever: Viral load. J Clin Virol, 75, 42-46.

    6. Hawman, D.W.,Feldmann, H., 2023. Crimean-Congo haemorrhagic fever virus. Nat Rev Microbiol, 21, 463-477.

    7. Kaya, S., Elaldi, N., Kubar, A., Gursoy, N., Yilmaz, M., Karakus, G., Gunes, T., Polat, Z., Gozel, M.G., Engin, A., Dokmetas, I., Bakir, M., Yilmaz, N.,Sencan, M., 2014. Sequential determination of serum viral titers, virus-specific IgG antibodies, and TNF-α, IL-6, IL-10, and IFN-γ levels in patients with Crimean-Congo hemorrhagic fever. BMC Infect Dis, 14, 416.

    8. Ozturk, B., Tutuncu, E., Kuscu, F., Gurbuz, Y., Sencan, I.,Tuzun, H., 2012. Evaluation of factors predictive of the prognosis in Crimean-Congo hemorrhagic fever: new suggestions. Int J Infect Dis, 16, e89-93.

    9. Rodriguez, S.E., Hawman, D.W., Sorvillo, T.E., O'neal, T.J., Bird, B.H., Rodriguez, L.L., Bergeron, E., Nichol, S.T., Montgomery, J.M., Spiropoulou, C.F.,Spengler, J.R., 2022. Immunobiology of Crimean-Congo hemorrhagic fever. Antiviral Res, 199, 105244.

    10. Semper, A.E., Olver, J., Warner, J., Cehovin, A., Fay, P.C., Hart, P.J., Golding, J.P., Benassi, V., Preziosi, M.P., Al-Asadi, K.H.R., Blumberg, L.H., De La Fuente, J., Elaldi, N., Fletcher, T., Formenty, P.B.H., Gouya, M.M., Gunther, S., Hewson, R., Jamil, B., Kobinger, G., Korukluoglu, G., Lempereur, L., Palacios, G., Papa, A., Pshenichnaya, N., Schmaljohn, C., Sow, S.O., Sprong, H., Vatansever, Z.,Brooks, T.J.G., 2024. Research and product development for Crimean-Congo haemorrhagic fever: priorities for 2024-30. Lancet Infect Dis, 24, 00656-x.

    11. Song, J.C., Zhang, W., Zhang, L., Yang, J., Zhang, J.H., Zhou, J., Wang, Q.S.,Li, W.Q., 2022. Consensus of Chinese experts on standardized evaluation of coagulation dysfunction in severe patients. Med J Chin PLA, 47, 107-117.

    12. Thrombosis and Hemostasis Group, Hematology Society of Chinese Medical Association, 2017. Consensus of Chinese experts on diagnosis of disseminated intravascular coagulation (version 2017). Chin J Hematol, 38, 361-363.

    13. Zivcec, M., Safronetz, D., Scott, D., Robertson, S., Ebihara, H.,Feldmann, H., 2013. Lethal Crimean-Congo hemorrhagic fever virus infection in interferon α/β receptor knockout mice is associated with high viral loads, proinflammatory responses, and coagulopathy. J Infect Dis, 207, 1909-1921.

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    A mouse model of Crimean-Congo hemorrhagic fever virus-induced coagulopathy

      Corresponding author: Yiwu Zhou, zhouyiwu@hust.edu.cn
      Corresponding author: Zhihong Hu, huzh@wh.iov.cn
      Corresponding author: Jia Liu, liujia@wh.iov.cn
    • a. State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China;
    • b. University of Chinese Academy of Sciences, Beijing, 100049, China;
    • c. Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, China

    Abstract: Highlights
    1. A mouse model for CCHFV-induced coagulopathy was developed and characterized using STAT1 knockout mice.
    2. High doses of CCHFV resulted in delayed tail bleeding time, shortened PT and APTT, and prolonged ELT.
    3. Histopathology showed thrombus formation in the liver and the spleen as well as intestinal hemorrhages.

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