Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity.
Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity.
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DOI：
10.1038/s41586-022-04474-x
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发表时间：
2022-03
期刊：
影响因子：
64.8
通讯作者：
Gupta RK
中科院分区：
文献类型：
--
作者：
Meng B;Abdullahi A;Ferreira IATM;Goonawardane N;Saito A;Kimura I;Yamasoba D;Gerber PP;Fatihi S;Rathore S;Zepeda SK;Papa G;Kemp SA;Ikeda T;Toyoda M;Tan TS;Kuramochi J;Mitsunaga S;Ueno T;Shirakawa K;Takaori-Kondo A;Brevini T;Mallery DL;Charles OJ;CITIID-NIHR BioResource COVID-19 Collaboration;Genotype to Phenotype Japan (G2P-Japan) Consortium;Ecuador-COVID19 Consortium;Bowen JE;Joshi A;Walls AC;Jackson L;Martin D;Smith KGC;Bradley J;Briggs JAG;Choi J;Madissoon E;Meyer KB;Mlcochova P;Ceron-Gutierrez L;Doffinger R;Teichmann SA;Fisher AJ;Pizzuto MS;de Marco A;Corti D;Hosmillo M;Lee JH;James LC;Thukral L;Veesler D;Sigal A;Sampaziotis F;Goodfellow IG;Matheson NJ;Sato K;Gupta RK
SARS-CoV-2 Omicron BA.1 变种于 2021 年出现，其刺突蛋白存在多个突变。在这里，我们表明，与 Delta 相比，Omicron 的刺突蛋白对 ACE2 具有更高的亲和力，并且其抗原性的显着变化增加了 Omicron 在两次剂量后逃避治疗性单克隆抗体和疫苗引发的多克隆中和抗体的能力。 mRNA 疫苗接种作为第三剂疫苗可挽救并扩大中和作用。重要的是，抗病毒药物瑞德西韦和莫努匹拉韦保留了针对 Omicron BA.1 的功效。 Omicron 和 Delta 病毒分离株在人鼻上皮培养物中的复制相似。然而，在肺细胞和肠道细胞中，Omicron 的复制速度较低。与 Delta 相比，Omicron 刺突蛋白的切割效率较低。根据刺突假型病毒检测，将复制的差异映射到病毒的进入效率。 Omicron 假型病毒进入特定细胞类型的缺陷与 TMPRSS2 较高的细胞 RNA 表达有效相关，并且 TMPRSS2 的删除对 Delta 进入的影响程度比 Omicron 更大。此外，针对特定进入途径的药物抑制剂证明，Omicron 尖峰不能有效地使用细胞蛋白酶 TMPRSS2，该蛋白酶通过质膜融合促进细胞进入，并且更大地依赖于通过内吞途径的细胞进入。与次优的 S1/S2 裂解和无法使用 TMPRSS2 一致，与 Delta 尖峰相比，Omicron 尖峰形成的合胞体明显受损。 Omicron 在 S1/S2 处的尖峰裂解效率较低，与细胞向性远离表达 TMPRSS2 的细胞的转变有关，从而影响发病机制的改变。 SARS-CoV-2 的 Omicron 变体的刺突蛋白对 ACE2 的亲和力比 Delta 更高，其抗原性的显着变化增加了 Omicron 逃避治疗和疫苗引起的中和抗体的能力。
The SARS-CoV-2 Omicron BA.1 variant emerged in 2021 and has multiple mutations in its spike protein. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis. The spike protein of the Omicron variant of SARS-CoV-2 has a higher affinity for ACE2 than Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic and vaccine-elicited neutralizing antibodies.
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DOI：
10.1093/infdis/jiab368
发表时间：
2021-09-17
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Ferreira IATM;Kemp SA;Datir R;Saito A;Meng B;Rakshit P;Takaori-Kondo A;Kosugi Y;Uriu K;Kimura I;Shirakawa K;Abdullahi A;Agarwal A;Ozono S;Tokunaga K;Sato K;Gupta RK;CITIID-NIHR BioResource COVID-19 Collaboration, Indian SARS-CoV-2 Genomics Consortium;Genotype to Phenotype Japan (G2P-Japan) Consortium
通讯作者：
Genotype to Phenotype Japan (G2P-Japan) Consortium
影响因子：
5.4
作者：
Heurich, Adeline;Hofmann-Winkler, Heike;Poehlmann, Stefan
通讯作者：
Poehlmann, Stefan
影响因子：
16.6
作者：
Cattin-Ortolá J;Welch LG;Maslen SL;Papa G;James LC;Munro S
通讯作者：
Munro S
影响因子：
64.8
作者：
Barnes CO;Jette CA;Abernathy ME;Dam KA;Esswein SR;Gristick HB;Malyutin AG;Sharaf NG;Huey-Tubman KE;Lee YE;Robbiani DF;Nussenzweig MC;West AP Jr;Bjorkman PJ
通讯作者：
Bjorkman PJ
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.