Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity
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Abstract
The SARS-CoV-2 Omicron BA.1 variant emerged in 2021 1 and has multiple mutations in its spike protein 2 . 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 pathways 3 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.
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SciScore for 10.1101/2021.12.17.473248: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources The consensus genome was translated to poly-proteins and the Spike gene was aligned to the original Wuhan strain using mafft v7.49018 with the -- globalpair --maxiterate 1000 flags. mafftsuggested: (MAFFT, RRID:SCR_011811)Further processing of steps involving minimisation and peptide bond building (after deletions for B. 1.617.2 and B. 1.529 spike) were performed using Gromacs toolkit. Gromacssuggested: (GROMACS, RRID:SCR_014565)The analysis was performed using Pyinteraph and the interaction plotter (pymol plugin) was used to map the interactions identified by Pyinteraph on the 3D-spike … SciScore for 10.1101/2021.12.17.473248: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources The consensus genome was translated to poly-proteins and the Spike gene was aligned to the original Wuhan strain using mafft v7.49018 with the -- globalpair --maxiterate 1000 flags. mafftsuggested: (MAFFT, RRID:SCR_011811)Further processing of steps involving minimisation and peptide bond building (after deletions for B. 1.617.2 and B. 1.529 spike) were performed using Gromacs toolkit. Gromacssuggested: (GROMACS, RRID:SCR_014565)The analysis was performed using Pyinteraph and the interaction plotter (pymol plugin) was used to map the interactions identified by Pyinteraph on the 3D-spike structure (Tiberti et al., 2014). pymolsuggested: (PyMOL, RRID:SCR_000305)Results from OddPub: Thank you for sharing your code.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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