The P681H Mutation in the Spike Glycoprotein of the Alpha Variant of SARS-CoV-2 Escapes IFITM Restriction and Is Necessary for Type I Interferon Resistance.
The P681H Mutation in the Spike Glycoprotein of the Alpha Variant of SARS-CoV-2 Escapes IFITM Restriction and Is Necessary for Type I Interferon Resistance.
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DOI：
10.1128/jvi.01250-22
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发表时间：
2022-12-14
影响因子：
5.4
通讯作者：
中科院分区：
文献类型：
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严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）新的主要关注变体（VOC）的出现威胁到全球对2019冠状病毒病（COVID-19）大流行的应对。其中，最初出现在英国的α变体（也称为B.1.1.7）在2021年上半年成为欧洲和北美大部分地区的主要变体。与祖先病毒相比，α的刺突（S）糖蛋白获得了7个突变和2个缺失，包括邻近多碱基切割位点的P681 H突变，这被认为可以增强S切割。在这里，我们表明，α刺突蛋白赋予人肺上皮细胞对β干扰素（IFN-β）的抗性水平。这与对干扰素诱导的跨膜蛋白2（IFITM 2）介导的进入限制的抗性和IFITM 3的显著感染增强相关。此外，P681 H突变对于α S中IFN-β抗性和IFITM环境依赖性抗性是必需的。P681 H降低了对内体组织蛋白酶的依赖性，与增强的细胞表面进入一致。然而，H681的回复并不减少裂解的尖峰掺入到颗粒中，表明其对弗林蛋白酶裂解下游的进入和IFN-β发挥作用。总的来说，我们认为，除了适应性免疫逃逸，与VOC相关的突变也可能通过适应抵抗先天免疫机制而赋予复制和/或传播优势。重要性越来越多的证据表明，SARS-CoV-2的变异体（VOC）进化以逃避人类免疫反应，人们的兴趣集中在逃避抗体的刺突蛋白的突变上。然而，对先天免疫应答的抗性对于有效的病毒复制和传播是必不可少的。在这里，我们表明，α（B.1.1.7）VOC的SARS-CoV-2是实质上更耐I型干扰素比亲本武汉样病毒。这与对抗病毒蛋白IFITM 2的抗性和由其特异性IFITM 3增强相关。其关键决定因素是S中邻近弗林蛋白酶切割位点的681位的脯氨酸至组氨酸的变化，其在α峰的背景下调节SARS-CoV-2的细胞进入途径。突变的逆转足以恢复干扰素和IFITM 2的敏感性，突出了SARS CoV-2的动态性质，因为它适应人类的先天免疫和适应性免疫。
The appearance of new dominant variants of concern (VOC) of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) threatens the global response to the coronavirus disease 2019 (COVID-19) pandemic. Of these, the alpha variant (also known as B.1.1.7), which appeared initially in the United Kingdom, became the dominant variant in much of Europe and North America in the first half of 2021. The spike (S) glycoprotein of alpha acquired seven mutations and two deletions compared to the ancestral virus, including the P681H mutation adjacent to the polybasic cleavage site, which has been suggested to enhance S cleavage. Here, we show that the alpha spike protein confers a level of resistance to beta interferon (IFN-β) in human lung epithelial cells. This correlates with resistance to an entry restriction mediated by interferon-induced transmembrane protein 2 (IFITM2) and a pronounced infection enhancement by IFITM3. Furthermore, the P681H mutation is essential for resistance to IFN-β and context-dependent resistance to IFITMs in the alpha S. P681H reduces dependence on endosomal cathepsins, consistent with enhanced cell surface entry. However, reversion of H681 does not reduce cleaved spike incorporation into particles, indicating that it exerts its effect on entry and IFN-β downstream of furin cleavage. Overall, we suggest that, in addition to adaptive immune escape, mutations associated with VOC may well also confer a replication and/or transmission advantage through adaptation to resist innate immune mechanisms. IMPORTANCE Accumulating evidence suggests that variants of concern (VOC) of SARS-CoV-2 evolve to evade the human immune response, with much interest focused on mutations in the spike protein that escape from antibodies. However, resistance to the innate immune response is essential for efficient viral replication and transmission. Here, we show that the alpha (B.1.1.7) VOC of SARS-CoV-2 is substantially more resistant to type I interferons than the parental Wuhan-like virus. This correlates with resistance to the antiviral protein IFITM2 and enhancement by its paralogue IFITM3. The key determinant of this is a proline-to-histidine change at position 681 in S adjacent to the furin cleavage site, which in the context of the alpha spike modulates cell entry pathways of SARS-CoV-2. Reversion of the mutation is sufficient to restore interferon and IFITM2 sensitivity, highlighting the dynamic nature of the SARS CoV-2 as it adapts to both innate and adaptive immunity in the humans.
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DOI：
10.1126/science.abd3072
发表时间：
2020-11-13
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Daly JL;Simonetti B;Klein K;Chen KE;Williamson MK;Antón-Plágaro C;Shoemark DK;Simón-Gracia L;Bauer M;Hollandi R;Greber UF;Horvath P;Sessions RB;Helenius A;Hiscox JA;Teesalu T;Matthews DA;Davidson AD;Collins BM;Cullen PJ;Yamauchi Y
通讯作者：
Yamauchi Y
鉴定 IFITM3 抗病毒作用所必需的内吞信号。
影响因子：
3.4
作者：
Jia R;Xu F;Qian J;Yao Y;Miao C;Zheng YM;Liu SL;Guo F;Geng Y;Qiao W;Liang C
通讯作者：
Liang C
影响因子：
5.8
作者：
Benlarbi, Mehdi;Laroche, Genevieve;Fink, Corby;Fu, Kathy;Mulloy, Rory P.;Phan, Alexandra;Ariana, Ardeshir;Stewart, Corina M.;Prevost, Jeremie;Beaudoin-Bussieres, Guillaume;Daniel, Redaet;Bo, Yuxia;El Ferri, Omar;Yockell-Lelievre, Julien;Stanford, William L.;Giguere, Patrick M.;Mubareka, Samira;Finzi, Andres;Dekaban, Gregory A.;Dikeakos, Jimmy D.;Cote, Marceline
通讯作者：
Cote, Marceline
影响因子：
8.8
作者：
Braun, Elisabeth;Hotter, Dominik;Sauter, Daniel
通讯作者：
Sauter, Daniel
DOI：
10.1073/pnas.2203760119
发表时间：
2022-08-09
影响因子：
11.1
作者：
通讯作者：
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