Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonism
ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve after its emergence. Given its importance in viral infection and vaccine development, mutations in the viral Spike gene have been studied extensively; however, the impact of mutations outside the Spike gene are...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Emerging Microbes and Infections |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2023.2209208 |
| _version_ | 1797652796383690752 |
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| author | Cody J. Bills Hongjie Xia John Yun-Chung Chen Jason Yeung Birte K. Kalveram David Walker Xuping Xie Pei-Yong Shi |
| author_facet | Cody J. Bills Hongjie Xia John Yun-Chung Chen Jason Yeung Birte K. Kalveram David Walker Xuping Xie Pei-Yong Shi |
| author_sort | Cody J. Bills |
| collection | DOAJ |
| description | ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve after its emergence. Given its importance in viral infection and vaccine development, mutations in the viral Spike gene have been studied extensively; however, the impact of mutations outside the Spike gene are poorly understood. Here, we report that a triple deletion (ΔSGF or ΔLSG) in nonstructural protein 6 (nsp6) independently acquired in Alpha and Omicron sublineages of SARS-CoV-2 augments nsp6-mediated antagonism of type-I interferon (IFN-I) signaling. Specifically, these triple deletions enhance the ability of mutant nsp6 to suppress phosphorylation of STAT1 and STAT2. A parental SARS-CoV-2 USA-WA1/2020 strain containing the nsp6 ΔSGF deletion (ΔSGF-WA1) shows reduced susceptibility to IFN-I treatment in vitro, outcompetes the parental strain in human primary airway cultures, and increases virulence in mice; however, the ΔSGF-WA1 virus is less virulent than the Alpha variant (which has the nsp6 ΔSGF deletion and additional mutations in other genes). Analyses of host responses from ΔSGF-WA1-infected mice and primary airway cultures reveal activation of pathways indicative of a cytokine storm. These results provide evidence that mutations outside the Spike protein affect virus-host interactions and may alter pathogenesis of SARS-CoV-2 variants in humans. |
| first_indexed | 2024-03-11T16:35:10Z |
| format | Article |
| id | doaj.art-56f69a925c4e4733a1fc4da4467f646a |
| institution | Directory Open Access Journal |
| issn | 2222-1751 |
| language | English |
| last_indexed | 2024-03-11T16:35:10Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Emerging Microbes and Infections |
| spelling | doaj.art-56f69a925c4e4733a1fc4da4467f646a2023-10-23T17:36:55ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512023-12-0112110.1080/22221751.2023.2209208Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonismCody J. Bills0Hongjie Xia1John Yun-Chung Chen2Jason Yeung3Birte K. Kalveram4David Walker5Xuping Xie6Pei-Yong Shi7Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USADepartment of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USADepartment of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USADepartment of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USADepartment of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USADepartment of Pathology, University of Texas Medical Branch, Galveston, TX, USADepartment of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USADepartment of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USAABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve after its emergence. Given its importance in viral infection and vaccine development, mutations in the viral Spike gene have been studied extensively; however, the impact of mutations outside the Spike gene are poorly understood. Here, we report that a triple deletion (ΔSGF or ΔLSG) in nonstructural protein 6 (nsp6) independently acquired in Alpha and Omicron sublineages of SARS-CoV-2 augments nsp6-mediated antagonism of type-I interferon (IFN-I) signaling. Specifically, these triple deletions enhance the ability of mutant nsp6 to suppress phosphorylation of STAT1 and STAT2. A parental SARS-CoV-2 USA-WA1/2020 strain containing the nsp6 ΔSGF deletion (ΔSGF-WA1) shows reduced susceptibility to IFN-I treatment in vitro, outcompetes the parental strain in human primary airway cultures, and increases virulence in mice; however, the ΔSGF-WA1 virus is less virulent than the Alpha variant (which has the nsp6 ΔSGF deletion and additional mutations in other genes). Analyses of host responses from ΔSGF-WA1-infected mice and primary airway cultures reveal activation of pathways indicative of a cytokine storm. These results provide evidence that mutations outside the Spike protein affect virus-host interactions and may alter pathogenesis of SARS-CoV-2 variants in humans.https://www.tandfonline.com/doi/10.1080/22221751.2023.2209208SARS-CoV-2variantsnsp6interferoncytokine storm |
| spellingShingle | Cody J. Bills Hongjie Xia John Yun-Chung Chen Jason Yeung Birte K. Kalveram David Walker Xuping Xie Pei-Yong Shi Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonism Emerging Microbes and Infections SARS-CoV-2 variants nsp6 interferon cytokine storm |
| title | Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonism |
| title_full | Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonism |
| title_fullStr | Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonism |
| title_full_unstemmed | Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonism |
| title_short | Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonism |
| title_sort | mutations in sars cov 2 variant nsp6 enhance type i interferon antagonism |
| topic | SARS-CoV-2 variants nsp6 interferon cytokine storm |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2023.2209208 |
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