Mak Nelly S C, Liu Jingyan, Zhang Dan, Taylor Jordan, Li Xiaomeng, Rahman Kazi, Chen Feiyu, Datta Siddhartha A K, Lai Kin Kui, Shi Zhengli, Temperton Nigel, Irving Aaron T, Compton Alex A, Sloan Richard D
Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom.
Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom.
PLoS Pathog. 2024 Dec 26;20(12):e1012763. doi: 10.1371/journal.ppat.1012763. eCollection 2024 Dec.
Species-specific interferon responses are shaped by the virus-host arms race. The human interferon-induced transmembrane protein (IFITM) family consists of three antiviral IFITM genes that arose by gene duplication. These genes restrict virus entry and are key players in antiviral interferon responses. The unique IFITM repertoires in different species influence their resistance to viral infections, but the role of IFITMs in shaping the enhanced antiviral immunity of reservoir bat species is unclear. Here, we identified an IFITM gene in Chinese rufous horseshoe bat, a natural host of severe acute respiratory syndrome (SARS)-related coronaviruses, that is alternatively spliced to produce two IFITM isoforms in native cells as shown by transcriptomics. These bat IFITMs have conserved structures in vitro as demonstrated by circular dichroism spectroscopy, yet they exhibit distinct antiviral specificities against influenza A virus, Nipah virus and coronaviruses including SARS-CoV, SARS-CoV-2 and MERS-CoV. In parallel with human IFITM1-3, bat IFITM isoforms localize to distinct sites of virus entry which influences their antiviral potency. Further bioinformatic analysis of IFITM repertoires in 206 mammals reveals that alternative splicing is a recurring strategy for IFITM diversification, albeit less widely adopted than gene duplication. These findings demonstrate that alternative splicing is a key strategy for evolutionary diversification in the IFITM family. Our study also highlights an example of convergent evolution where species-specific selection pressures led to expansion of the IFITM family through multiple means, underscoring the importance of IFITM diversity as a component of innate immunity.
物种特异性干扰素反应是由病毒与宿主的军备竞赛塑造的。人类干扰素诱导跨膜蛋白（IFITM）家族由三个通过基因复制产生的抗病毒IFITM基因组成。这些基因限制病毒进入，是抗病毒干扰素反应的关键参与者。不同物种中独特的IFITM组成影响它们对病毒感染的抗性，但IFITM在塑造宿主蝙蝠物种增强的抗病毒免疫力中的作用尚不清楚。在这里，我们在中国棕果蝠（严重急性呼吸综合征（SARS）相关冠状病毒的天然宿主）中鉴定出一个IFITM基因，转录组学显示该基因在天然细胞中通过可变剪接产生两种IFITM异构体。如圆二色光谱所示，这些蝙蝠IFITM在体外具有保守结构，但它们对甲型流感病毒、尼帕病毒和包括SARS-CoV、SARS-CoV-2和MERS-CoV在内的冠状病毒表现出不同的抗病毒特异性。与人类IFITM1-3一样，蝙蝠IFITM异构体定位于病毒进入的不同位点，这影响了它们的抗病毒效力。对206种哺乳动物中IFITM组成的进一步生物信息学分析表明，可变剪接是IFITM多样化的一种反复出现的策略，尽管其采用程度不如基因复制广泛。这些发现表明可变剪接是IFITM家族进化多样化的关键策略。我们的研究还突出了一个趋同进化的例子，即物种特异性选择压力通过多种方式导致IFITM家族的扩张，强调了IFITM多样性作为先天免疫组成部分的重要性。
