SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility
Summary: 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 pro...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-09-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723010884 |
| _version_ | 1827822376853700608 |
|---|---|
| author | 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. Jung Young Ki Choi |
| author_facet | 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. Jung Young Ki Choi |
| author_sort | Se-Mi Kim |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-12T01:56:07Z |
| format | Article |
| id | doaj.art-5e952bf83ad14ff8886740478ba9fdf0 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T01:56:07Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-5e952bf83ad14ff8886740478ba9fdf02023-09-08T04:33:13ZengElsevierCell Reports2211-12472023-09-01429113077SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibilitySe-Mi Kim0Eun-Ha Kim1Mark Anthony B. Casel2Young-Il Kim3Rong Sun4Mi-Jeong Kwak5Ji-Seung Yoo6Mina Yu7Kwang-Min Yu8Seung-Gyu Jang9Rare Rollon10Jeong Ho Choi11Juryeon Gil12Kiyoung Eun13Hyunggee Kim14Armin Ensser15Jungwon Hwang16Min-Suk Song17Myung Hee Kim18Jae U. Jung19Young Ki Choi20Center for Study of Emerging and Re-emerging Viruses, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of KoreaCenter for Study of Emerging and Re-emerging Viruses, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of KoreaCollege of Medicine and Medical Research Institute, Chungbuk National University, Cheongju 28644, Republic of KoreaCenter for Study of Emerging and Re-emerging Viruses, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of KoreaDepartment of Cancer Biology, Infection Biology Program, and Global Center for Pathogens and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USADepartment of Cancer Biology, Infection Biology Program, and Global Center for Pathogens and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USACenter for Study of Emerging and Re-emerging Viruses, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of KoreaCenter for Study of Emerging and Re-emerging Viruses, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of KoreaCollege of Medicine and Medical Research Institute, Chungbuk National University, Cheongju 28644, Republic of KoreaCollege of Medicine and Medical Research Institute, Chungbuk National University, Cheongju 28644, Republic of KoreaCollege of Medicine and Medical Research Institute, Chungbuk National University, Cheongju 28644, Republic of KoreaCollege of Medicine and Medical Research Institute, Chungbuk National University, Cheongju 28644, Republic of KoreaCollege of Medicine and Medical Research Institute, Chungbuk National University, Cheongju 28644, Republic of KoreaInstitute of Animal Molecular Biotechnology, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea; Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seongbuk-gu, Seoul 02841, Republic of KoreaInstitute of Animal Molecular Biotechnology, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea; Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seongbuk-gu, Seoul 02841, Republic of KoreaInstitute for Clinical and Molecular Virology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, GermanyInfection and Immunity Research Laboratory, Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaCollege of Medicine and Medical Research Institute, Chungbuk National University, Cheongju 28644, Republic of KoreaInfection and Immunity Research Laboratory, Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, KoreaDepartment of Cancer Biology, Infection Biology Program, and Global Center for Pathogens and Human Health Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Corresponding authorCenter for Study of Emerging and Re-emerging Viruses, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of Korea; College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju 28644, Republic of Korea; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723010884CP: Immunology |
| spellingShingle | 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. Jung Young Ki Choi SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility Cell Reports CP: Immunology |
| title | SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility |
| title_full | SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility |
| title_fullStr | SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility |
| title_full_unstemmed | SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility |
| title_short | SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility |
| title_sort | sars cov 2 variants with nsp12 p323l g671s mutations display enhanced virus replication in ferret upper airways and higher transmissibility |
| topic | CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723010884 |
| work_keys_str_mv | AT semikim sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT eunhakim sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT markanthonybcasel sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT youngilkim sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT rongsun sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT mijeongkwak sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT jiseungyoo sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT minayu sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT kwangminyu sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT seunggyujang sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT rarerollon sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT jeonghochoi sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT juryeongil sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT kiyoungeun sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT hyunggeekim sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT arminensser sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT jungwonhwang sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT minsuksong sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT myungheekim sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT jaeujung sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility AT youngkichoi sarscov2variantswithnsp12p323lg671smutationsdisplayenhancedvirusreplicationinferretupperairwaysandhighertransmissibility |