SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility
With the emergence of multiple predominant SARS-CoV-2 variants, it becomes important to have a comprehensive assessment of their viral fitness and transmissibility. Here, we demonstrate that natural temperature differences between the upper (33°C) and lower (37°C) respiratory tract have profound eff...
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Veröffentlicht in: | Cell reports (Cambridge) 2023-09, Vol.42 (9), p.113077-113077, Article 113077 |
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Zusammenfassung: | With the emergence of multiple predominant SARS-CoV-2 variants, it becomes important to have a comprehensive assessment of their viral fitness and transmissibility. Here, we demonstrate that natural temperature differences between the upper (33°C) and lower (37°C) respiratory tract have profound effects on SARS-CoV-2 replication and transmissibility. Specifically, SARS-CoV-2 variants containing the NSP12 mutations P323L or P323L/G671S exhibit enhanced RNA-dependent RNA polymerase (RdRp) activity at 33°C compared with 37°C and high transmissibility. Molecular dynamics simulations and microscale thermophoresis demonstrate that the NSP12 P323L and P323L/G671S mutations stabilize the NSP12-NSP7-NSP8 complex through hydrophobic effects, leading to increased viral RdRp activity. Furthermore, competitive transmissibility assay reveals that reverse genetic (RG)-P323L or RG-P323L/G671S NSP12 outcompetes RG-WT (wild-type) NSP12 for replication in the upper respiratory tract, allowing markedly rapid transmissibility. This suggests that NSP12 P323L or P323L/G671S mutation of SARS-CoV-2 is associated with increased RdRp complex stability and enzymatic activity, promoting efficient transmissibility.
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•NSP12-P323L or P323L/G671S alters polymerase kinetics in a temperature-dependent manner•NSP12 mutations increase interaction with the NPS8 reinforcing the vRNP assembly•SARS-CoV-2 containing the NSP12 mutations promotes high viral titers in upper airways•NSP12 mutations enhance transmissibility of variant SARS-CoV-2
Kim and colleagues investigate the impact of NSP12 mutations found among SARS-CoV-2 variants and demonstrate that NSP12-P323L and P323L/G671S substitutions significantly enhance virus replication in ferret upper airways, leading to rapid transmissions. Further analyses demonstrate that NSP12 mutations increase the stability of the NSP12-NSP-7-NSP8 complex, resulting in enhanced RdRp activity. |
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ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2023.113077 |