SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility

Se Mi Kim, Eun Ha Kim, Mark Anthony B. Casel, Young Il Kim, Rong Sun, Mi Jeong Kwak, Ji Seung Yoo, Mina Yu, Kwang Min Yu, Seung Gyu Jang, Rare Rollon, Jeong Ho Choi, Juryeon Gil, Kiyoung Eun, Hyunggee Kim, Armin Ensser, Jungwon Hwang, Min Suk Song, Myung Hee Kim, Jae U. JungYoung Ki Choi

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


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.

Original languageEnglish
Article number113077
JournalCell Reports
Issue number9
Publication statusPublished - 2023 Sept 26

Bibliographical note

Publisher Copyright:
© 2023 The Authors


  • CP: Immunology
  • NSP12 mutation
  • RNA-dependent RNA polymerase
  • SARS-CoV-2
  • ferret
  • transmissibility

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology


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