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Evolution of enhanced innate immune evasion by SARS-CoV-2.

ABSTRACT: The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission^1,2. 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.

SUBMITTER: Thorne LG

PROVIDER: S-EPMC8850198 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Evolution of enhanced innate immune evasion by SARS-CoV-2.

Thorne Lucy G LG Bouhaddou Mehdi M Reuschl Ann-Kathrin AK Zuliani-Alvarez Lorena L Polacco Ben B Pelin Adrian A Batra Jyoti J Whelan Matthew V X MVX Hosmillo Myra M Fossati Andrea A Ragazzini Roberta R Jungreis Irwin I Ummadi Manisha M Rojc Ajda A Turner Jane J Bischof Marie L ML Obernier Kirsten K Braberg Hannes H Soucheray Margaret M Richards Alicia A Chen Kuei-Ho KH Harjai Bhavya B Memon Danish D Hiatt Joseph J Rosales Romel R McGovern Briana L BL Jahun Aminu A Fabius Jacqueline M JM White Kris K Goodfellow Ian G IG Takeuchi Yasu Y Bonfanti Paola P Shokat Kevan K Jura Natalia N Verba Klim K Noursadeghi Mahdad M Beltrao Pedro P Kellis Manolis M Swaney Danielle L DL García-Sastre Adolfo A Jolly Clare C Towers Greg J GJ Krogan Nevan J NJ

Nature 20211223 7897

The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission<sup>1,2</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<sup>3</sup> suppress innate immu ...[more]

PMID: 34942634

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Project description:Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant B.1.1.529 (Omicron) has rapidly become the dominant strain, with an unprecedented number of mutations within its spike gene. However, it remains unknown whether these variants have alterations in their entry efficiency, host tropism, and sensitivity to neutralizing antibodies and entry inhibitors. In this study, we found that Omicron spike has evolved to escape neutralization by three-dose inactivated-vaccine-elicited immunity but remains sensitive to an angiotensin-converting enzyme 2 (ACE2) decoy receptor. Moreover, Omicron spike could use human ACE2 with a slightly increased efficiency while gaining a significantly increased binding affinity for a mouse ACE2 ortholog, which exhibits limited binding with wild-type (WT) spike. Furthermore, Omicron could infect wild-type C57BL/6 mice and cause histopathological changes in the lungs. Collectively, our results reveal that evasion of neutralization by vaccine-elicited antibodies and enhanced human and mouse ACE2 receptor engagement may contribute to the expanded host range and rapid spread of the Omicron variant. IMPORTANCE The recently emerged SARS-CoV-2 Omicron variant with numerous mutations in the spike protein has rapidly become the dominant strain, thereby raising concerns about the effectiveness of vaccines. Here, we found that the Omicron variant exhibits a reduced sensitivity to serum neutralizing activity induced by a three-dose inactivated vaccine but remains sensitive to entry inhibitors or an ACE2-Ig decoy receptor. Compared with the ancestor strain isolated in early 2020, the spike protein of Omicron utilizes the human ACE2 receptor with enhanced efficiency while gaining the ability to utilize mouse ACE2 for cell entry. Moreover, Omicron could infect wild-type mice and cause pathological changes in the lungs. These results reveal that antibody evasion, enhanced human ACE2 utilization, and an expanded host range may contribute to its rapid spread.

Dataset Information

Evolution of enhanced innate immune evasion by SARS-CoV-2.

Publications

Evolution of enhanced innate immune evasion by SARS-CoV-2.

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