Journal
CELL REPORTS
Volume 42, Issue 9, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2023.113077
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This study demonstrates that natural temperature differences between upper and lower respiratory tracts impact the replication and transmission of SARS-CoV-2. Mutations P323L or P323L/G671S enhance the activity of RNA-dependent RNA polymerase (RdRp) at lower temperatures and increase transmissibility. The stability of the NSP12-NSP7-NSP8 complex is increased by these mutations, leading to efficient viral replication and transmission.
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 & DEG;C) and lower (37 & DEG;C) respiratory tract have profound effects on SARS-CoV2 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 & DEG;C compared with 37 & DEG;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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