Evolution of enhanced innate immune evasion by SARS-CoV-2
<jats:title>Abstract</jats:title><jats:p>The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission<jats:sup>1,2</jats:sup>. Although much effort has focused on the characterization of changes in the spike protein in...
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2022
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| Online Access: | https://hdl.handle.net/1721.1/143721 |
| _version_ | 1811090044429008896 |
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| author | Kellis, Manolis |
| author2 | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory |
| author_facet | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Kellis, Manolis |
| author_sort | Kellis, Manolis |
| collection | MIT |
| description | <jats:title>Abstract</jats:title><jats:p>The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission<jats:sup>1,2</jats:sup>. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant<jats:sup>3</jats:sup> suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6—all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection<jats:sup>4</jats:sup>. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants.</jats:p> |
| first_indexed | 2024-09-23T14:31:18Z |
| format | Article |
| id | mit-1721.1/143721 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T14:31:18Z |
| publishDate | 2022 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1437212023-08-07T18:34:40Z Evolution of enhanced innate immune evasion by SARS-CoV-2 Kellis, Manolis Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory <jats:title>Abstract</jats:title><jats:p>The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission<jats:sup>1,2</jats:sup>. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant<jats:sup>3</jats:sup> suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6—all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection<jats:sup>4</jats:sup>. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants.</jats:p> 2022-07-13T17:16:14Z 2022-07-13T17:16:14Z 2022 2022-07-13T17:11:40Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/143721 Kellis, Manolis. 2022. "Evolution of enhanced innate immune evasion by SARS-CoV-2." Nature, 602 (7897). en 10.1038/S41586-021-04352-Y Nature Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | Kellis, Manolis Evolution of enhanced innate immune evasion by SARS-CoV-2 |
| title | Evolution of enhanced innate immune evasion by SARS-CoV-2 |
| title_full | Evolution of enhanced innate immune evasion by SARS-CoV-2 |
| title_fullStr | Evolution of enhanced innate immune evasion by SARS-CoV-2 |
| title_full_unstemmed | Evolution of enhanced innate immune evasion by SARS-CoV-2 |
| title_short | Evolution of enhanced innate immune evasion by SARS-CoV-2 |
| title_sort | evolution of enhanced innate immune evasion by sars cov 2 |
| url | https://hdl.handle.net/1721.1/143721 |
| work_keys_str_mv | AT kellismanolis evolutionofenhancedinnateimmuneevasionbysarscov2 |