Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant

Thorne, Lucy; Bouhaddou, Mehdi; Reuschl, Ann-Kathrin; Zuliani-Alvarez, Lorena; Polacco, Benjamin J.; Pelin, Adrian; Batra, Jyoti; Whelan, Matt; Ummadi, Manisha R.; Roic, Ajda; Turner, Jane; Obernier, Kirsten; Braberg, Hannes; Soucheray, Margaret; Richards, Alicia; Chen, Kuei‐Ho; Harjai, Bhavya; Memon, Danish; Hosmillo, Myra; Hiatt, Joseph; Jahun, Aminu S.; Goodfellow, Ian; Noursadeghi, Mahdad; Fabius, Jacqueline M.; Shokat, Kevan M.; Jura, Natalia; Verba, Kliment A.; Beltrão, Pedro; Swaney, Danielle L.; Garcı́a-Sastre, Adolfo; Jolly, Clare; Towers, Greg J.; Krogan, Nevan J.

doi:10.1101/2021.06.06.446826

Cited by 102 publications

(87 citation statements)

References 68 publications

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“…The nsp6 Ser 106 _Phe 108 del is predicted to be located at a loop in the interface between a transmembrane helix and the ER lumen based on a preliminary structural analysis of the model generated by the AlphaFold2 system (Figure 7d), and we hypothesize that the deletion may affect functional interactions of nsp6 with other proteins. In addition, in agreement with the enhanced suppression of innate immune response reported for B.1.1.7 (Thorne et al 2021), changes in immune-antagonists, such as nsp6…”

Section: S Pro 681supporting

confidence: 82%

“…For example, Thorne et al recently showed that the B.1.1.7 VOC suppresses the innate immune response by host cells in vitro and attributed it to the increased transcription of the orf9b gene, nested within the gene coding the nucleocapsid protein. (Thorne et al 2021), although they could not rule out the possibility that this was due to nsp6 Ser 106 _Phe del.…”

Section: Discussionmentioning

confidence: 98%

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Rapid expansion of SARS-CoV-2 variants of concern is a result of adaptive epistasis

Garvin

Prates

Romero

et al. 2021

Preprint

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The SARS-CoV-2 pandemic has entered an alarming new phase with the emergence of the variants of concern (VOC), P.1, B.1.351, and B.1.1.7, in late 2020, and B.1.427, B.1.429, and B.1.617, in 2021. Substitutions in the spike glycoprotein (S), such as Asn501Tyr and Glu484Lys, are likely key in several VOC. However, Asn501Tyr had been circulating for months in earlier strains and Glu484Lys is not found in B.1.1.7, indicating that they do not fully explain those fast-spreading variants. Here we use a computational systems biology approach to process more than 900,000 SARS-CoV-2 genomes and map spatiotemporal relationships, revealing other critical attributes of these variants. Comparisons to earlier dominant mutations and protein structural analyses indicate that the increased transmission is promoted by the combination of functionally complementary mutations in S and in other regions of the SARS-CoV-2 proteome. We report that the VOC have in common mutations in non-S proteins involved in immune-antagonism and replication performance, such as the nonstructural proteins 6 and 13, suggesting a convergent evolution of the virus. Critically, we propose that recombination events among divergent coinfecting haplotypes greatly accelerates the emergence of VOC by bringing together cooperative mutations and explaining the remarkably high mutation load of B.1.1.7. Therefore, extensive community distribution of SARS-CoV-2 increases the probability of future recombination events, further accelerating the evolution of the virus. This study reinforces the need for a global response to stop COVID-19 and future pandemics.

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Section: S Pro 681supporting

confidence: 82%

Section: Discussionmentioning

confidence: 98%

Rapid expansion of SARS-CoV-2 variants of concern is a result of adaptive epistasis

Garvin

Prates

Romero

et al. 2021

Preprint

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“…Additionally, we could show that the substitution of the serine at position 53 by a phosphomimetic glutamate residue in Orf9b prevented its interaction with the C-terminal domain of TOM70 in vitro and in intact mammalian cells. During the preparation of this manuscript, a preprint that was published confirmed our finding that Orf9b binding is dependent on the state of its serine in position 53 [43]. In addition, the authors observed the suppression of host kinase activity in the early stages of infection, which likely represents a way of innate immune evasion for the virus.…”

Section: Implications Of Orf9b Binding To Tom70 For Health and Diseasesupporting

confidence: 70%

Phosphorylation of SARS-CoV-2 Orf9b Regulates Its Targeting to Two Binding Sites in TOM70 and Recruitment of Hsp90

Brandherm

Kobaš

Klöhn

et al. 2021

IJMS

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SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the causative agent of the COVID19 pandemic. The SARS-CoV-2 genome encodes for a small accessory protein termed Orf9b, which targets the mitochondrial outer membrane protein TOM70 in infected cells. TOM70 is involved in a signaling cascade that ultimately leads to the induction of type I interferons (IFN-I). This cascade depends on the recruitment of Hsp90-bound proteins to the N-terminal domain of TOM70. Binding of Orf9b to TOM70 decreases the expression of IFN-I; however, the underlying mechanism remains elusive. We show that the binding of Orf9b to TOM70 inhibits the recruitment of Hsp90 and chaperone-associated proteins. We characterized the binding site of Orf9b within the C-terminal domain of TOM70 and found that a serine in position 53 of Orf9b and a glutamate in position 477 of TOM70 are crucial for the association of both proteins. A phosphomimetic variant Orf9bS53E showed drastically reduced binding to TOM70 and did not inhibit Hsp90 recruitment, suggesting that Orf9b–TOM70 complex formation is regulated by phosphorylation. Eventually, we identified the N-terminal TPR domain of TOM70 as a second binding site for Orf9b, which indicates a so far unobserved contribution of chaperones in the mitochondrial targeting of the viral protein.

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“…Furthermore, the L452R mutation, which augments stability/expression (59), increases viral replication kinetics relative to the ancestral virus (71). The enhanced ability of B.1.1.7 to antagonize host innate immunity through upregulation of orf6 and orf9b was suggested to have participated in the success of this variant (72). It is possible that B.1.617.2 evolved a similar strategy to reach global domination warranting further studies to uncover the contribution of innate immune antagonism to the continued emergence of variants with greater transmissibility.…”

Section: And Biolayer Interferometry (Fig 2i Fig S4x Tablementioning

confidence: 98%

Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants

McCallum

Walls

Sprouse

et al. 2021

Preprint

110

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Worldwide SARS-CoV-2 transmission leads to the recurrent emergence of variants, such as the recently described B.1.617.1 (kappa), B.1.617.2 (delta) and B.1.617.2+ (delta+). The B.1.617.2 (delta) variant of concern is causing a new wave of infections in many countries, mostly affecting unvaccinated individuals, and has become globally dominant. We show that these variants dampen the in vitro potency of vaccine-elicited serum neutralizing antibodies and provide a structural framework for describing the impact of individual mutations on immune evasion. Mutations in the B.1.617.1 (kappa) and B.1.617.2 (delta) spike glycoproteins abrogate recognition by several monoclonal antibodies via alteration of key antigenic sites, including an unexpected remodeling of the B.1.617.2 (delta) N-terminal domain. The binding affinity of the B.1.617.1 (kappa) and B.1.617.2 (delta) receptor-binding domain for ACE2 is comparable to the ancestral virus whereas B.1.617.2+ (delta+) exhibits markedly reduced affinity. We describe a previously uncharacterized class of N-terminal domain-directed human neutralizing monoclonal antibodies cross-reacting with several variants of concern, revealing a possible target for vaccine development.

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Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant

Cited by 102 publications

References 68 publications

Rapid expansion of SARS-CoV-2 variants of concern is a result of adaptive epistasis

Rapid expansion of SARS-CoV-2 variants of concern is a result of adaptive epistasis

Phosphorylation of SARS-CoV-2 Orf9b Regulates Its Targeting to Two Binding Sites in TOM70 and Recruitment of Hsp90

Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants

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