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

Kim SM, Kim EH, Casel MAB, Kim YI, Sun R, Kwak MJ, Yoo JS, Yu M, Yu KM, Jang SG, Rollon R, Choi JH, Gil J, Eun K, Kim H, Enßer A, Hwang J, Song MS, Kim MH, Jung JU, Choi YK (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Cell Reports Elsevier (Cell Press)

Book Volume: 42

Article Number: 113077

Journal Issue: 9

DOI: 10.1016/j.celrep.2023.113077

Abstract

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.

Authors with CRIS profile

Armin Enßer Institute of Clinical and Molecular Virology

Involved external institutions

Institute for Basic Science KR Korea, Republic of (KR) Chungbuk National University (CBNU) / 충북대학교 KR Korea, Republic of (KR) Cleveland Clinic US United States (USA) (US) Korea University KR Korea, Republic of (KR) Korea Research Institute of Bioscience and Biotechnology(KRIBB) KR Korea, Republic of (KR)

How to cite

APA:

Kim, S.M., Kim, E.H., Casel, M.A.B., Kim, Y.I., Sun, R., Kwak, M.J.,... Choi, Y.K. (2023). SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility. Cell Reports, 42(9). https://doi.org/10.1016/j.celrep.2023.113077

MLA:

Kim, Se Mi, et al. "SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility." Cell Reports 42.9 (2023).

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