Evolution of enhanced innate immune evasion by SARS-CoV-2
Author:
Thorne Lucy G.ORCID, Bouhaddou Mehdi, Reuschl Ann-Kathrin, Zuliani-Alvarez Lorena, Polacco BenORCID, Pelin Adrian, Batra Jyoti, Whelan Matthew V. X., Hosmillo Myra, Fossati AndreaORCID, Ragazzini RobertaORCID, Jungreis IrwinORCID, Ummadi Manisha, Rojc Ajda, Turner Jane, Bischof Marie L., Obernier KirstenORCID, Braberg HannesORCID, Soucheray Margaret, Richards Alicia, Chen Kuei-HoORCID, Harjai Bhavya, Memon DanishORCID, Hiatt Joseph, Rosales Romel, McGovern Briana L.ORCID, Jahun AminuORCID, Fabius Jacqueline M., White KrisORCID, Goodfellow Ian G.ORCID, Takeuchi Yasu, Bonfanti PaolaORCID, Shokat KevanORCID, Jura NataliaORCID, Verba KlimORCID, Noursadeghi MahdadORCID, Beltrao Pedro, Kellis ManolisORCID, Swaney Danielle L.ORCID, García-Sastre AdolfoORCID, Jolly ClareORCID, Towers Greg J.ORCID, Krogan Nevan J.ORCID
Abstract
AbstractThe emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. 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) variant3 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 infection4. 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.
Publisher
Springer Science and Business Media LLC
Subject
Multidisciplinary
Reference68 articles.
1. Volz, E. et al. Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England. Nature 593, 266–269 (2021). 2. Davies, N. G. et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Science 372 eabg3055 (2021). 3. Galloway, S. E. et al. Emergence of SARS-CoV-2 B.1.1.7 lineage—United States, December 29, 2020–January 12, 2021. MMWR Morb. Mortal. Wkly Rep. 70, 95–99 (2021). 4. Calistri, P. et al. Infection sustained by lineage B.1.1.7 of SARS-CoV-2 is characterised by longer persistence and higher viral RNA loads in nasopharyngeal swabs. Int. J. Infect. Dis. 105, 753–755 (2021). 5. Foster, T. L. et al. Resistance of transmitted founder HIV-1 to IFITM-mediated restriction. Cell Host Microbe 20, 429–442 (2016).
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