Elevated interferon-induced transmembrane protein 3 in platelets and megakaryocytes suppresses Crimean-Congo hemorrhagic fever viral infection by interacting with glycoprotein Gc

Jingyuan Zhang; Yaohui Fang; Chenhui Lin; Xiaoli Wu; Chaoxiong Yue; Fei Deng; Shu Shen

doi:10.1016/j.virs.2025.05.002

June 2025

. doi: 10.1016/j.virs.2025.05.002

Citation: Jingyuan Zhang, Yaohui Fang, Chenhui Lin, Xiaoli Wu, Chaoxiong Yue, Fei Deng, Shu Shen. Elevated interferon-induced transmembrane protein 3 in platelets and megakaryocytes suppresses Crimean-Congo hemorrhagic fever viral infection by interacting with glycoprotein Gc .VIROLOGICA SINICA, 2025, 40(3) : 361-373. http://dx.doi.org/10.1016/j.virs.2025.05.002

血小板和巨核细胞中干扰素诱导的跨膜蛋白3上调与糖蛋白Gc互作抑制克里米亚-刚果出血热病毒感染

张敬媛 ^a,b ,
方耀辉 ^a,b ,
林晨辉 ^a,b ,
吴晓丽 ^a ,
岳超雄 ^a ,
邓菲 ^a,, ,
沈姝 ^a,c,,

a 中国科学院武汉病毒研究所, 病毒学与生物安全重点实验室;
b 中国科学院大学;
c 湖北省江夏实验室;
d 新疆维吾尔自治区媒介生物传染病重点实验室

通讯作者： 邓菲, df@wh.iov.cn; 沈姝, shenshu@wh.iov.cn
收稿日期： 2025-01-18
录用日期： 2025-05-08

摘要

克里米亚-刚果出血热（CCHF）是一种由CCHF病毒（CCHFV）感染引起的高致病性出血热疾病。患者血小板减少导致严重出血，病死率高达30%，但其致病机制仍不清楚。除了参与止血凝血，血小板在识别病原体和介导免疫反应方面也发挥着至关重要的作用。本研究通过CCHFV感染小鼠的血小板转录组分析，发现CCHFV感染导致血小板功能异常，并在血小板差异化表达基因中发现干扰素诱导的跨膜蛋白3（IFITM3）显著上调。CCHFV能感染人巨核细胞系MEG-01（血小板的亲本细胞系）。尽管感染效率低于CCHFV敏感的人胚胎肾细胞HEK293，MEG-01细胞仍能并支持CCHFV复制和产生子代病毒，同时MEG-01中IFITM3蛋白表达水平显著增高。进一步实验表明：IFITM3过表达的MEG-01细胞可有效抑制CCHFV感染，而IFITM3敲除后则促进病毒感染。IFITM3与CCHFV糖蛋白Gc之间存在相互作用抑制CCHFV入侵细胞。此外，IFITM3的CIL-TMD结构域对这种互作非常重要。上述结果表明，IFITM3是重要的宿主限制因子，在CCHFV感染过程中发挥抗病毒作用。血小板中IFITM3表达升高，很可能是血小板对CCHFV感染发挥抗病毒应答的重要机制，进而导致血小板消耗而减少。研究结果促进了对CCHF相关血小板应答机制的理解，为深入解析CCHF致病机制、发展新的治疗策略提供重要理论参考。
- 克里米亚-刚果出血热病毒
- , 干扰素诱导的跨膜蛋白3
- , 血小板
- , 巨核细胞

Elevated interferon-induced transmembrane protein 3 in platelets and megakaryocytes suppresses Crimean-Congo hemorrhagic fever viral infection by interacting with glycoprotein Gc

Jingyuan Zhang ^a,b ,
Yaohui Fang ^a,b ,
Chenhui Lin ^a,b ,
Xiaoli Wu ^a ,
Chaoxiong Yue ^a ,
Fei Deng ^a,, ,
Shu Shen ^a,c,,

a. Key Laboratory of Virology and Biosafety and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430070, China;
b. University of Chinese Academy of Sciences, Beijing, 100049, China;
c. Xinjiang Key Laboratory of Vector-borne Infectious Diseases, Urumqi, 830002, China

Corresponding author: Fei Deng, df@wh.iov.cn Shu Shen, shenshu@wh.iov.cn
Received Date: 18 January 2025
Accepted Date: 08 May 2025

Abstract

Crimean-Congo hemorrhagic fever (CCHF) is a hemorrhagic fever caused by infection with the CCHF virus (CCHFV) and has a mortality rate of up to 30 %. Thrombocytopenia is a hallmark of CCHF; however, the mechanisms underlying this manifestation remain poorly understood. In addition to hemostasis, platelets play a crucial role in recognizing pathogens and mediating immune responses. We investigated the mechanisms underlying thrombocytopenia associated with CCHFV infection by analyzing the platelet transcriptome in mice. Interferon-induced transmembrane protein 3 (IFITM3), a known antiviral factor, was significantly upregulated. The role of IFITM3 in response to CCHFV infection was characterized using the human megakaryoblast cell line MEG-01, considered a parental cell line of platelets. Although the CCHFV infection rate was limited, MEG-01 cells maintained the infection and replication of CCHFV, leading to increased IFITM3 protein expression. We demonstrated that IFITM3 overexpression efficiently inhibited CCHFV infection, whereas IFITM3 knockout promoted viral infection. An interaction between IFITM3 and the CCHFV glycoprotein Gc was identified, which suppressed CCHFV entry into cells. The IFITM3 CIL-TMD domain is critical for this interaction. These results suggest that IFITM3 is a restriction factor and plays an antiviral role during CCHFV infection. Elevated expression of IFITM3 in platelets indicates that this could be a common mechanism by which platelets protect against viruses, including CCHFV, which may reduce platelet consumption and destruction caused by CCHFV infection. These findings provide valuable insights into the pathogenesis of CCHF-associated thrombocytopenia and offer foundational theoretical support for future therapeutic strategies.
- Crimean-Congo hemorrhagic fever virus (CCHFV)
- , Interferon-induced transmembrane protein 3 (IFITM3)
- , Platelet
- , Megakaryocytes

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