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Publication Detail
Evolution of enhanced innate immune evasion by SARS-CoV-2
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Thorne LG, Bouhaddou M, Reuschl AK, Zuliani-Alvarez L, Polacco B, Pelin A, Batra J, Whelan MVX, Hosmillo M, Fossati A, Ragazzini R, Jungreis I, Ummadi M, Rojc A, Turner J, Bischof ML, Obernier K, Braberg H, Soucheray M, Richards A, Chen KH, Harjai B, Memon D, Hiatt J, Rosales R, McGovern BL, Jahun A, Fabius JM, White K, Goodfellow IG, Takeuchi Y, Bonfanti P, Shokat K, Jura N, Verba K, Noursadeghi M, Beltrao P, Kellis M, Swaney DL, GarcĂ­a-Sastre A, Jolly C, Towers GJ, Krogan NJ
  • Publication date:
    17/02/2022
  • Journal:
    Nature
  • Status:
    Published
  • Print ISSN:
    0028-0836
Abstract
Emergence of SARS-CoV-2 variants of concern (VOCs) suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on characterisation of spike changes in VOCs, mutations outside spike likely contribute to adaptation. Here we used unbiased abundance proteomics, phosphoproteomics, RNAseq and viral replication assays to show that isolates of the Alpha (B.1.1.7) variant3 more effectively suppress innate immune responses in airway epithelial cells, compared to first wave isolates. We found that Alpha has dramatically increased subgenomic RNA and protein levels of 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 required for RNA sensing adaptor MAVS activation. 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 Alpha transmission, and may increase in vivo replication and duration of infection4. The importance of mutations outside Spike in adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the Delta and Omicron N/Orf9b regulatory regions.
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Div of Infection & Immunity
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Div of Infection & Immunity
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Div of Infection & Immunity
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Div of Infection & Immunity
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Div of Infection & Immunity
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Div of Infection & Immunity
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Div of Infection & Immunity
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