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

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Title
SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility
Author(s)
Se-Mi Kim; Eun-Ha Kim; Casel, Mark Anthony B.; Young-Il Kim; Sun, Rong; Kwak, Mi-Jeong; Ji-Seung Yoo; Mina Yu; Yu, Kwang-Min; Jang, Seung-Gyu; Rollon, Rare; Choi, Jeong Ho; Gil, Juryeon; Eun, Kiyoung; Kim, Hyunggee; Ensser, Armin; Hwang, Jungwon; Song, Min-Suk; Kim, Myung Hee; Jung, Jae U.; Young Ki Choi
Publication Date
2023-09
Journal
Cell Reports, v.42, no.9
Publisher
Cell Press
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. © 2023 The Authors
URI
https://pr.ibs.re.kr/handle/8788114/13995
DOI
10.1016/j.celrep.2023.113077
ISSN
2211-1247
Appears in Collections:
Korea Virus Research Institute(한국바이러스기초연구소) > Center for Study of Emerging and Re-emerging Viruses(신변종 바이러스 연구센터) > 1. Journal Papers (저널논문)
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