Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA; World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
Cell Rep. 2022 May 17;39(7):110829. doi: 10.1016/j.celrep.2022.110829. Epub 2022 Apr 29.
We report that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta spike mutation P681R plays a key role in the Alpha-to-Delta variant replacement during the coronavirus disease 2019 (COVID-19) pandemic. Delta SARS-CoV-2 efficiently outcompetes the Alpha variant in human lung epithelial cells and primary human airway tissues. The Delta spike mutation P681R is located at a furin cleavage site that separates the spike 1 (S1) and S2 subunits. Reverting the P681R mutation to wild-type P681 significantly reduces the replication of the Delta variant to a level lower than the Alpha variant. Mechanistically, the Delta P681R mutation enhances the cleavage of the full-length spike to S1 and S2, which could improve cell-surface-mediated virus entry. In contrast, the Alpha spike also has a mutation at the same amino acid (P681H), but the cleavage of the Alpha spike is reduced compared with the Delta spike. Our results suggest P681R as a key mutation in enhancing Delta-variant replication via increased S1/S2 cleavage.
我们报告称，严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的刺突突变 P681R 在 2019 年冠状病毒病（COVID-19）大流行期间的 Alpha 至 Delta 变体替代中发挥了关键作用。Delta SARS-CoV-2 在人肺上皮细胞和原代人气道组织中有效地取代了 Alpha 变体。Delta 刺突突变 P681R 位于弗林裂解位点，该位点将刺突 1（S1）和 S2 亚单位分开。将 P681R 突变回复为野生型 P681 可显著降低 Delta 变体的复制水平，使其低于 Alpha 变体。从机制上讲，Delta P681R 突变增强了全长刺突向 S1 和 S2 的裂解，这可以改善细胞表面介导的病毒进入。相比之下，Alpha 刺突在相同的氨基酸（P681H）处也有一个突变，但与 Delta 刺突相比，Alpha 刺突的裂解减少了。我们的研究结果表明，P681R 是通过增加 S1/S2 裂解来增强 Delta 变体复制的关键突变。
