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

Lucy Thorne1, Mehdi Bouhaddou, Ann-Kathrin Reuschl2, Lorena Zuliani-Alvarez, Benjamin J. Polacco, Adrian Pelin, Jyoti Batra, Matthew Whelan2, Manisha Ummadi, Ajda Roic, Jane Turner2, Kirsten Obernier, Hannes Braberg, Margaret Soucheray, Alicia L. Richards, Kuei-Ho Chen, Bhavya Harjai, Danish Memon3, Myra Hosmillo4, Joseph Hiatt, Aminu S Jahun4, Ian Goodfellow4, Mahdad Noursadeghi2, Jacqueline M. Fabius, Kevan M. Shokat, Natalia Jura, Kliment A. Verba1, Kliment A. Verba5, Pedro Beltrao3, Danielle L. Swaney, Adolfo García-Sastre, Clare Jolly2, Greg J. Towers2, Nevan J. Krogan •
University of California, San Francisco1, University College London2, European Bioinformatics Institute3, University of Cambridge4, University of California, Berkeley5
07 Jun 2021-bioRxiv (Cold Spring Harbor Laboratory)-
TL;DR: In this article, the authors used unbiased abundance proteomics, phosphoproteomics, mRNA sequencing and viral replication assays to show that B.1.7 isolates more effectively suppress host innate immune responses in airway epithelial cells.
Abstract: Emergence of SARS-CoV-2 variants, including the globally successful B.1.1.7 lineage, suggests viral adaptations to host selective pressures resulting in more efficient transmission. Although much effort has focused on Spike adaptation for viral entry and adaptive immune escape, B.1.1.7 mutations outside Spike likely contribute to enhance transmission. Here we used unbiased abundance proteomics, phosphoproteomics, mRNA sequencing and viral replication assays to show that B.1.1.7 isolates more effectively suppress host innate immune responses in airway epithelial cells. We found that B.1.1.7 isolates have dramatically increased subgenomic RNA and protein levels of Orf9b and Orf6, both 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, and Orf9b binding and activity was regulated via phosphorylation. We conclude that B.1.1.7 has evolved beyond the Spike coding region to more effectively antagonise host innate immune responses through upregulation of specific subgenomic RNA synthesis and increased protein expression of key innate immune antagonists. We propose that more effective innate immune antagonism increases the likelihood of successful B.1.1.7 transmission, and may increase in vivo replication and duration of infection.
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1
1
Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant
Lucy G Thorne
1
☨, Mehdi Bouhaddou
2,3,4,5
☨, Ann-Kathrin Reuschl
1
☨, Lorena Zuliani-Alvarez
2,3,4,5
☨,
Ben Polacco
2,3,4,5
, Adrian Pelin
2,3,4,5
, Jyoti Batra
2,3,4,5
, Matthew V.X. Whelan
1
,
Manisha
Ummadi
2,3,4,5
, Ajda Rojc
2,3,4,5
, Jane Turner
1
, Kirsten Obernier
2,3,4,5
, Hannes Braberg
2,3,4,5
, Margaret
Soucheray
2,3,4,5
, Alicia Richards
2,3,4,5
, Kuei-Ho Chen
2,3,4,5
, Bhavya Harjai
2,3,4,5
, Danish Memon
7
,
Myra Hosmillo
8
, Joseph Hiatt
2,3,4,5
, Aminu Jahun
8
, Ian G. Goodfellow
8
, Jacqueline M. Fabius
2,3,4,5
,
Kevan Shokat
2,3,4,5,6
, Natalia Jura
2,3,5,9
, Klim Verba
2,3,5
, Mahdad Noursadeghi
1
, Pedro Beltrao
2,7
,
Danielle L. Swaney
2,3,4,5
, Adolfo Garcia-Sastre
2,10,11,12
, Clare Jolly
1
*, Greg J. Towers
1
*, and Nevan
J. Krogan
2,3,4,5
*
☨ These authors contributed equally
*Corresponding authors. Email: nevan.krogan@ucsf.edu (NJK), g.towers@ucl.ac.uk (GJT), and
c.jolly@ucl.ac.uk
1
Division of Infection and Immunity, University College London, London, WC1E 6BT, United
Kingdom
2
Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco,
CA 94158, USA
3
Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco,
CA, 94158, USA
4
J. David Gladstone Institutes, San Francisco, CA 94158, USA
5
Department of Cellular and Molecular Pharmacology, University of California, San Francisco,
San Francisco, CA 94158, USA
6
Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
7
European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome
Genome Campus, Hinxton, Cambridge, UK.
8
Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke's
Hospital, Hills Road, Cambridge CB2 2QQ, UK
9
Cardiovascular Research Institute, University of California - San Francisco, San Francisco, CA
94158, U.S.A.
10
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029,
USA
11
Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai,
New York, NY, 10029, USA
12
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029,
USA
.CC-BY 4.0 International licenseavailable under a
was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprint (whichthis version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.06.446826doi: bioRxiv preprint
2
2
Abstract
Emergence of SARS-CoV-2 variants, including the globally successful B.1.1.7 lineage, suggests
viral adaptations to host selective pressures resulting in more efficient transmission. Although
much effort has focused on Spike adaptation for viral entry and adaptive immune escape, B.1.1.7
mutations outside Spike likely contribute to enhance transmission. Here we used unbiased
abundance proteomics, phosphoproteomics, mRNA sequencing and viral replication assays to
show that B.1.1.7 isolates more effectively suppress host innate immune responses in airway
epithelial cells. We found that B.1.1.7 isolates have dramatically increased subgenomic RNA and
protein levels of Orf9b and Orf6, both 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, and Orf9b binding and activity was
regulated via phosphorylation. We conclude that B.1.1.7 has evolved beyond the Spike coding
region to more effectively antagonise host innate immune responses through upregulation of
specific subgenomic RNA synthesis and increased protein expression of key innate immune
antagonists. We propose that more effective innate immune antagonism increases the likelihood
of successful B.1.1.7 transmission, and may increase in vivo replication and duration of infection.
Main
The SARS-CoV-2 B.1.1.7 lineage was detected in the United Kingdom in September 2020 and
quickly became the dominant variant worldwide
1
. Epidemiologically, B.1.1.7 human-to-human
transmission is superior to other SARS-CoV-2 lineages
2,3
, making it a variant of concern (VOC),
threatening public health containment measures
4
. B.1.1.7 infection has been associated with
enhanced clinical severity in the community in the UK, although a clear association with increased
mortality has not yet emerged
2,3,5,6
.
B.1.1.7 is defined by a constellation of 23 mutations
7
: 17 that alter protein sequence (14 non-
synonymous mutations and 3 deletions) and 6 synonymous mutations (Fig. 1a). Protein coding
changes concentrate in Spike, which facilitates viral entry through interaction with the human
receptor ACE2
8
. This has led the field to focus on understanding viral escape from wave one
(early-lineage) driven adaptive immunity and its implications for infection control and vaccine
development. Fortunately, despite adaptation of Spike, B.1.1.7 remains sensitive to vaccine- and
infection-induced neutralising antibodies
9–11
. B.1.1.7 variant of concern (VOC)-defining mutations
outside Spike suggest that Spike-independent adaptation to host may contribute to the B.1.1.7
transmission advantage. Most B.1.1.7 coding changes map to non-structural proteins Nsp3,
Nsp6, accessory protein Orf8 and nucleocapsid protein (N), all of which have been shown to
modulate the innate immune response
12–16
. Furthermore, it is unclear whether any of the B.1.1.7-
specific mutations impact the expression levels of viral proteins. In sum, the impact of these
additional mutations on viral replication, transmission and pathogenesis has not been
characterised.
Innate immune responses can exert strong selective pressure during viral transmission
17–19
and
play an important role in determining clinical outcomes to SARS-CoV-2 infection
20–22
. We
therefore reasoned that B.1.1.7 may have evolved to enhance innate immune escape. We and
others have recently shown that infection of naturally permissive Calu-3 human lung epithelial
.CC-BY 4.0 International licenseavailable under a
was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprint (whichthis version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.06.446826doi: bioRxiv preprint
3
3
cells with a wave one SARS-CoV-2 lineage B isolate (BetaCoV/Australia/VIC01/2020, VIC)
induces a robust but delayed innate response, driven by activation of RNA sensors RIG-I and
MDA5
23
. A delayed response, compared to rapid viral RNA replication, suggests effective innate
immune antagonism and evasion by SARS-CoV-2 early in infection
13,24
. Furthermore, the gene
expression changes observed during late innate responses in infected Calu-3 cells reflect the
overarching inflammatory signatures observed at the site of infection and those associated with
severe COVID-19
25–28
. Here, we used the Calu-3 cell model to evaluate differences between
B.1.1.7 and wave one SARS-CoV-2 viruses.
Comparative analysis of virus replication kinetics and interferon induction
We compared replication and innate immune activation for B.1.1.7 and two first wave (early
lineage) isolates, B lineage isolate BetaCoV/Australia/VIC01/2020 (VIC) and B.1.13 lineage
isolate hCoV-19/England/IC19/2020 (IC19) (Fig. 1a) in Calu-3 lung epithelial cells. Input dose was
normalised using viral genome copies measured by RT-qPCR for the envelope (E) coding region.
We found that B.1.1.7 replication was comparable to both wave one isolates at high and low
multiplicity of infection (MOI), measuring intracellular E copies, positivity for nucleocapsid protein
and infectious virion production by TCID50 on Hela-ACE2 cells (Fig. 1b, 1c). We observed a small
but significant increase in N positivity for B.1.1.7 (Fig. 1b, 1c), which we explain later in the context
of differences in viral protein expression.
Identical replication of all three isolates enabled direct comparison of the innate immune response
without differences in the amount of viral RNA produced, the principal pathogen associated
molecular pattern (PAMP)
23
, being a confounding factor. We found that B.1.1.7 infection led to
lower levels of IFNβ expression and secretion, at both high and low MOI (Fig. 1d, 1e). Similar
replication, but reduced IFNβ induction by B.1.1.7 was confirmed with two additional independent
B.1.1.7 isolates (Fig. 1f), suggesting consistent enhancement of innate immune antagonism, or
evasion, for B.1.1.7 lineage isolates.
As IFN resistance correlates with enhanced transmission of other pandemic viruses
17,18
, we
compared sensitivity to IFNβ inhibition of B.1.1.7 and first wave isolates. B.1.1.7 was consistently
less sensitive to IFNβ pre-treatment over a wide dose range, compared to first wave isolate VIC
(lineage B) (Fig. 1g), suggesting that B.1.1.7 infection not only induces less IFNβ (Fig. 1d, 1e) but
that it is also less sensitive to its effects. Interestingly, wave one IC19 (B.1.13) showed a similar
reduction in IFNβ sensitivity as B.1.1.7. This may be due to the shared Spike mutation D614G in
IC19 and B.1.1.7, but not VIC, which is associated with enhanced transmissibility and increased
entry efficiency
29–31
. Indeed, D614G has been associated with resistance to a range of Type I and
III IFNs across several SARS-CoV-2 lineages, and contributes to the enhanced IFN-evasion of
B.1.1.7
32
. Type I IFN restriction of SARS-CoV-2 is mediated in part by interferon induced
membrane protein 2 (IFITM2) suppression of viral entry, and IFITM2 sensitivity is influenced by
the Spike sequence
33,34
. We therefore focused on characterising the mechanism of enhanced
antagonism of the innate response which was unique to the B.1.1.7 lineage.
.CC-BY 4.0 International licenseavailable under a
was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprint (whichthis version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.06.446826doi: bioRxiv preprint
4
4
Figure 1. SARS-CoV-2 B.1.1.7 antagonises innate immune activation more efficiently than early-
lineage isolates. a. SARS-CoV-2 viruses compared in this study. Protein coding changes in B.1.1.7
.CC-BY 4.0 International licenseavailable under a
was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprint (whichthis version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.06.446826doi: bioRxiv preprint
5
5
(red), IC19 (grey) and VIC (blue) are indicated in comparison to the Wuhan-Hu-1 reference genome
(MN908947). B.1.1.7 changes include 23 lineage defining mutations, plus additional changes compared
to Wuhan-Hu-1, totalling 29. b and c. Calu-3 cells were infected with either (b) 5000 E copies/cell or (c)
5 E copies/cell of B.1.1.7, VIC and IC19. Measurements of replication of SARS-CoV-2 genomic and
subgenomic E RNAs (RT-qPCR) (left), % infection by intracellular nucleocapsid positivity (centre) or
infectious virion production by TCID50/ml (right) over time are shown. d and e. Fold induction of IFNβ
gene expression and protein secretion over time from cells in (b) and (c) respectively. f. Replication
(24hpi), IFNβ induction (24hpi) and IFNβ secretion (48hpi) by multiple independent B.1.1.7 isolates
compared to IC19 and VIC at 250 E copies/cell. g. SARS-CoV-2 infection at 2000 E copies/cell after 8h
pre-treatment with IFNβ at the indicated concentrations. Infection is shown as intracellular N levels
normalised to untreated controls at 24hpi. Data shown are mean +/- SEM of one of three representative
experiments performed in triplicate. Statistical comparisons are performed by Two Way ANOVA
(a,b,c,d,g) or One Way ANOVA with a Tukey post-comparison test (f). Blue stars indicate comparison
between B.1.1.7 and VIC (blue lines and symbols), grey stars indicate comparison between B.1.1.7 and
IC19 (grey lines and symbols). * (p<0.05), ** (p<0.01), *** (p<0.001), **** (p<0.0001). ns: non-significant.
E: viral envelope gene. Hpi: hours post infection.
Global proteomic and genomic analyses reveal enhanced innate immune suppression by
B.1.1.7
To compare cellular host responses to SARS-CoV-2 variants, we performed global mass
spectrometry-based protein abundance and phosphorylation profiling (i.e. phosphoproteomics)
as well as total RNAseq on infected Calu-3 cells at 10 and 24 hours post infection (hpi) (Fig. 2a,
Table S1). The proteomic analysis was performed using a data-independent acquisition (DIA)
approach, which decreases sample-to-sample and time point variability in peptide detection over
the traditional data-dependent acquisition (DDA) mode, strengthening the comparative potential
of these datasets (see Methods). Compared to mock infection, we observed robust changes in
RNA abundance and protein phosphorylation after infection, with fewer changes at the level of
protein abundance (Fig. S1a). After quality control data filtering was performed (see Methods),
principal components analysis (PCA; Fig. S1b) and Pearson’s correlation (Fig. S1c) confirmed
strong correlation between biological replicates, time points, and conditions. On average, we
quantified 15,000-16,000 mRNA transcripts above background levels (Fig. S1d), 33,000-40,000
peptides mapping to 3,600-4,000 proteins for protein abundance (Fig. S1e), and 22,000-30,000
phosphorylated peptides mapping to 3,200-3,800 proteins for phosphoproteomics (Fig. S1f).
Gene set pathway enrichment
35
analysis comparing B.1.1.7 to wave one isolates VIC and IC19
highlighted innate immune system-related pathways among the top 5 terms for all three data types
(RNA, protein abundance, and phosphorylation) (Fig. 2b, S1g-i, Table S2). Top scoring terms
were related to interferon alpha beta signalling and cytokine/chemokine signalling, and most
predominantly enriched for the RNA and protein phosphorylation datasets (Fig. 2b). Concordantly,
in addition to the reduction of IFNβ production (Fig 1d, 1e, 1f), B.1.1.7 infection resulted in reduced
induction of interferon-stimulated genes (ISGs) measured in the RNAseq and protein abundance
datasets using a predefined set of ISGs
36
(detailed in the Methods, Table S3). This was evident
at 10 and 24hpi at the RNA level (Fig. 2c-d, S2a, S2c) and at 24hpi for protein (Fig. 2d, S2b). For
a subset of genes (CXCL10, IFIT2, MX1, IFIT1, and RSAD2), we confirmed reduced ISG
.CC-BY 4.0 International licenseavailable under a
was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprint (whichthis version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.06.446826doi: bioRxiv preprint
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A pneumonia outbreak associated with a new coronavirus of probable bat origin

[...]

Peng Zhou1, Xing-Lou Yang1, Xian Guang Wang2, Ben Hu1, Lei Zhang1, Wei Zhang1, Hao Rui Si1, Yan Zhu1, Bei Li1, Chao Lin Huang2, Hui-Dong Chen2, Jing Chen1, Yun Luo1, Hua Guo1, Ren Di Jiang1, Meiqin Liu1, Ying Chen1, Xu Rui Shen1, Xi Wang1, Xiao Shuang Zheng1, Kai Zhao1, Quanjiao Chen1, Fei Deng1, Lin Lin Liu3, Bing Yan1, Fa Xian Zhan3, Yan-Yi Wang1, Gengfu Xiao1, Zhengli Shi1 •
Chinese Academy of Sciences1, Wuhan Jinyintan Hospital2, Centers for Disease Control and Prevention3
03 Feb 2020-Nature
TL;DR: Identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China, and it is shown that this virus belongs to the species of SARSr-CoV, indicates that the virus is related to a bat coronav virus.
Abstract: Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1–4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5–7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV. Characterization of full-length genome sequences from patients infected with a new coronavirus (2019-nCoV) shows that the sequences are nearly identical and indicates that the virus is related to a bat coronavirus.

16,857 citations

Journal Article•DOI•
Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR.

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Victor M. Corman1, Olfert Landt, Marco Kaiser, Richard Molenkamp2, Adam Meijer, Daniel K.W. Chu3, Tobias Bleicker1, Sebastian Brünink1, Julia Schneider1, Marie Luisa Schmidt1, Daphne G.J.C. Mulders2, Bart L. Haagmans2, Bas van der Veer, Sharon van den Brink, Lisa Wijsman, Gabriel Goderski, Jean Louis Romette, Joanna Ellis4, Maria Zambon4, Malik Peiris3, Herman Goossens5, Chantal B.E.M. Reusken, Marion Koopmans2, Christian Drosten1 •
Charité1, Erasmus University Rotterdam2, University of Hong Kong3, Public Health England4, University of Antwerp5
23 Jan 2020-Eurosurveillance
TL;DR: A validated diagnostic workflow for 2019-nCoV is presented, its design relying on close genetic relatedness of 2019- nCoV with SARS coronavirus, making use of synthetic nucleic acid technology.
Abstract: Background The ongoing outbreak of the recently emerged novel coronavirus (2019-nCoV) poses a challenge for public health laboratories as virus isolates are unavailable while there is growing evidence that the outbreak is more widespread than initially thought, and international spread through travellers does already occur. Aim We aimed to develop and deploy robust diagnostic methodology for use in public health laboratory settings without having virus material available. Methods Here we present a validated diagnostic workflow for 2019-nCoV, its design relying on close genetic relatedness of 2019-nCoV with SARS coronavirus, making use of synthetic nucleic acid technology. Results The workflow reliably detects 2019-nCoV, and further discriminates 2019-nCoV from SARS-CoV. Through coordination between academic and public laboratories, we confirmed assay exclusivity based on 297 original clinical specimens containing a full spectrum of human respiratory viruses. Control material is made available through European Virus Archive – Global (EVAg), a European Union infrastructure project. Conclusion The present study demonstrates the enormous response capacity achieved through coordination of academic and public laboratories in national and European research networks.

6,229 citations

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