Abstract：
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne hemorrhagic fever disease with high fatality rate of 10%-20%. Vaccines or specific therapeutic measures remain lacking. Human interferon inducible transmembrane protein 3 (hIFITM3) is a broad-spectrum antiviral factor targeting viral entry. However, the antiviral activity of hIFITM3 against SFTS virus (SFTSV) and the functional mechanism of IFITM3 remains unclear. Here we demonstrate that endogenous IFITM3 provides protection against SFTSV infection and participates in the anti-SFTSV effect of type Ⅰ and Ⅲ interferons (IFNs). IFITM3 overexpression exhibits anti-SFTSV function by blocking Gn/Gc-mediated viral entry and fusion. Further studies showed that IFITM3 binds SFTSV Gc directly and its intramembrane domain (IMD) is responsible for this interaction and restriction of SFTSV entry. Mutation of two neighboring cysteines on IMD weakens IFITM3-Gc interaction and attenuates the antiviral activity of IFITM3, suggesting that IFITM3-Gc interaction may partly mediate the inhibition of SFTSV entry. Overall, our data demonstrate for the first time that hIFITM3 plays a critical role in the IFNs-mediated anti-SFTSV response, and uncover a novel mechanism of IFITM3 restriction of SFTSV infection, highlighting the potential of clinical intervention on SFTS disease.
摘要：
严重发热伴血小板减少综合征（SFTS）是一种新兴的蜱传出血热疾病，病死率高达10％-20％。仍然缺乏疫苗或特定的治疗措施。人干扰素诱导跨膜蛋白3（hIFITM3）是一种靶向病毒进入的广谱抗病毒因子。然而,hIFITM3对SFTS病毒(SFTSV)的抗病毒活性及其作用机制尚不清楚.在这里，我们证明了内源性IFITM3对SFTSV感染具有保护作用，并参与了Ⅰ型和Ⅲ型干扰素（IFNs）的抗SFTSV作用。IFITM3过表达通过阻断Gn/Gc介导的病毒进入和融合而表现出抗SFTSV功能。进一步的研究表明，IFITM3直接结合SFTSVGc，其膜内结构域（IMD）负责这种相互作用和限制SFTSV进入。IMD上两个相邻半胱氨酸的突变削弱了IFITM3-Gc相互作用并减弱了IFITM3的抗病毒活性，表明IFITM3-Gc相互作用可能部分介导了SFTSV进入的抑制。总的来说,我们的数据首次表明hIFITM3在IFN介导的抗SFTSV反应中起关键作用，并揭示了IFITM3限制SFTSV感染的新机制，强调临床干预SFTS疾病的潜力。
