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A Prenylated Dsrna Sensor Protects Against Severe COVID-19 and Is Absent in Horseshoe Bats

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A Prenylated Dsrna Sensor Protects Against Severe COVID-19 and Is Absent in Horseshoe Bats medRxiv preprint doi: https://doi.org/10.1101/2021.05.05.21256681; this version posted May 9, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . @WilsonlabCVR Wickenhagen et al., A Prenylated dsRNA Sensor Protects Against Severe COVID-19 and is ABsent in Horseshoe Bats A Prenylated dsRNA Sensor Protects on global health, culture and prosperity. SARS-CoV-2 is Against Severe COVID-19 and is Absent in particularly sensitive to inhibition by type I interferons (IFNs) and there is great interest in understanding how individual Horseshoe Bats IFN-stimulated genes (ISGs) inhibit SARS-CoV-2, as type I IFNs play a major role in governing COVID-19 disease Arthur Wickenhagen1, Elena Sugrue1*, Spyros Lytras1*, 1* 1 1 outcome. Specifically, inborn errors (Zhang et al., 2020) Srikeerthana Kuchi , Matthew L Turnbull , Colin Loney , and single nucleotide polymorphisms (Pairo-Castineira et 1 1 1 Vanessa Herder , Jay Allan , Innes Jarmson , Natalia al., 2020) within the IFN system are linked with more severe 1 1 1 Cameron-Ruiz , Margus Varjak , Rute M Pinto , Douglas G COVID-19. Moreover, neutralizing anti-IFN autoantibodies 1 1 1 Stewart , Simon Swingler , Marko Noerenberg , Edward J likely prevent host IFN responses from controlling SARS- 2 2 1 D Greenwood , Thomas W M Crozier , Quan Gu , Sara CoV-2 replication, again resulting in severe COVID-19 3 3 4 Clohisey , Bo Wang , Fabio Trindade Maranhão Costa , disease (Bastard et al., 2020). Accordingly, recombinant 5 6 Monique Freire Santana , Luiz Carlos de Lima Ferreira , IFNs have therapeutic potential (Monk et al., 2021) 7 8 ISARIC4C investigators , Joao Luiz Da Silva Filho , although the timing of IFN responses or the administration Matthias Marti8, Richard J Stanton9, Eddie C Y Wang9, 1 1 of recombinant IFNs is likely critical (Channappanavar et Alfredo Castello-Palomares , Antonia Ho , Kenneth al., 2016). 3,7 1 1 Baillie , Ruth F Jarrett , David L Robertson , Massimo We sought to better understand the protective role 1 2 1 Palmarini , Paul J Lehner , Suzannah J Rihn , Sam J that IFNs play in COVID-19. We hypothesized that allelic 1,# Wilson . and spliced variation in individual antiviral defenses might underlie the differential susceptibility to severe COVID-19 1MRC–University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, University of Glasgow, UK observed in different individuals. To identify the ISG 2Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey products that inhibit SARS-CoV-2, we used arrayed ISG Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0AW, UK. expression screening to identify effectors with anti-SARS- 3Roslin Institute, University of Edinburgh, United Kingdom CoV-2 potential (Kane et al., 2016; Schoggins et al., 2011). 4Laboratory of Tropical Diseases – Prof. Luiz Jacintho da Silva, Department of We first confirmed that SARS-CoV-2 was IFN-sensitive in Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, SP, Brazil transformed human lung A549 cells modified to express the 5Department of Education and Research, Oncology Control Centre of Amazonas SARS-CoV-2 receptor ACE2 and the protease TMPRSS2 State – FCECON, Manaus, AM, Brazil; Tropical Medicine Foundation Dr. Heitor (Hoffmann et al., 2020; Rihn et al., 2021). These cells Vieira Dourado, Manaus, AM, Brazil 6Department of Pathology and Forensic Medicine, Tropical Medicine Foundation supported the efficient replication of SARS-CoV-2 and IFN Dr. Heitor Vieira Dourado, Manaus, AM, Brazil pre-treatment attenuated multiple variants (including 7ISARIC4C investigators 8Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and B.1.1.7) in an endpoint CPE assay (well-clearance (Rihn et Inflammation, University of Glasgow, UK al., 2021)) (Figure 1A). Thus, A549 cells were deemed 9Division of Infection & Immunity, Cardiff University, Cardiff, United Kingdom suitable for ISG expression screens. Because exogenously expressed ISGs can trigger *These authors contributed equally to this work antiviral gene expression programs (Kane et al., 2016), we Running title: Disrupted bat OAS1 sensitized SARS-CoV-2 to prenylated OAS1 in humans selected transformed ACE2-expressing, IRF3-deficient A549 cells (A549 Npro ACE2), which possess an # Address correspondence to: Sam J. Wilson attenuated ability to produce IFN (Hale et al., 2009) as the Email: [email protected] Tel: +44 (0) 141 330 4557; Fax +44 (0) 141 330 3520 background for the screens. We transduced these cells with an arrayed library of lentiviral vector-encoded ISGs in a 96- Abstract well plate format (one ISG per well), using a library of >500 Cell autonomous antiviral defenses can inhibit the human ISGs and a similar library of >350 rhesus macaque replication of viruses and reduce transmission and disease ISGs (Kane et al., 2016)(supplementary Figure 1A-C). The severity. To better understand the antiviral response to macaque ISGs were included as they increased the total SARS-CoV-2, we used interferon-stimulated gene (ISG) number of ISGs under consideration. Importantly, ~2/3 of expression screening to reveal that OAS1, through RNase the ISGs examined could potentially be relevant to L, potently inhibits SARS-CoV-2. We show that while some betacoronavirus infection (Parkinson et al., people can express a prenylated OAS1 variant, that is 2020)(supplementary Figure 1D,E). In order to capture membrane-associated and blocks SARS-CoV-2 infection, inhibition that might occur at any stage of the virus lifecycle, other people express a cytosolic, nonprenylated OAS1 we used a GFP-encoding recombinant SARS-CoV-2 (Thi variant which does not detect SARS-CoV-2 (determined by Nhu Thao et al., 2020) and measured the ability of each the splice-acceptor SNP Rs10774671). Alleles encoding individual ISG to inhibit SARS-CoV-2 at 14 hours (early) nonprenylated OAS1 predominate except in people of and 40 hours (late) postinfection. Using this approach, we African descent. Importantly, in hospitalized patients, identified a number of candidate anti-SARS-CoV-2 expression of prenylated OAS1 was associated with effectors (Figure 1C). All candidates that conferred >2-fold protection from severe COVID-19, suggesting this antiviral inhibition at early and late timepoints or only at late defense is a major component of a protective antiviral timepoints were considered further using a series of response. Remarkably, approximately 55 million years ago, independent confirmatory ‘miniscreens’. The magnitude of retrotransposition ablated the OAS1 prenylation signal in protection conferred by each ISG at early and late horseshoe bats (the presumed source of SARS-CoV-2). timepoints was assessed using ACE2-positive cells in the Thus, SARS-CoV-2 never had to adapt to evade this presence or absence of IRF3 (Figure 1D and defense. As prenylated OAS1 is widespread in animals, the Supplementary Figure 1F-J). In addition, we sought to billions of people that lack a prenylated OAS1 could make subtract nonspecific inhibitors of SARS-CoV-2 by humans particularly vulnerable to the spillover of identifying ISGs that triggered a polygenic ‘antiviral state’ coronaviruses from horseshoe bats. (Figure 1E) or caused cytotoxicity (Figure 1F). Following these confirmatory and negative selection screens, we Introduction and Results identified six candidate antiviral effectors that robustly NOTE:Severe This preprint acute reports respiratory new research syndrome that has coronavirus not been certified 2 inhibitedby peer review SARS and- CoVshould-2 notwithout be used inducing to guide substantialclinical practice. toxicity (SARS-CoV-2), which causes COVID-19, emerged in or inducing ISRE expression. human populations in 2019 and has left an indelible mark 1 medRxiv preprint doi: https://doi.org/10.1101/2021.05.05.21256681; this version posted May 9, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . @WilsonlabCVR Wickenhagen et al., A Prenylated dsRNA Sensor Protects Against Severe COVID-19 and is ABsent in Horseshoe Bats The candidate effectors included known antiviral (Rusinova et al., 2013), analyzed their basal expression in genes such as the IFN-inducible short isoform (isoform 4) respiratory and gastrointestinal tracts (GTEx) (figure 2E) of NCOA7, which inhibits influenza A viruses (IAVs) (Doyle and assessed their transcript abundance in post-mortem et al., 2018), and OAS1, a dsRNA sensor capable of lung tissue from COVID-19 patients (Figure 1F and activating RNase L (Donovan et al., 2013; Han et al., 2014). Supplementary Figure 2). In addition, we examined the We also identified UNC93B1, a polytopic membrane protein genomic locus of each candidate effector for SNPs that may required for TLR trafficking (Kim et al., 2008; Majer et al., be associated with increased susceptibility to infection 2019) as well as SCARB2, a virus receptor (Yamayoshi et and/or severe disease (Figure 2G and Supplementary al., 2009) involved in cholesterol transport (Heybrock et al., Figure 2). Following these analyses, we focused our 2019; Neculai et al., 2013). In addition, we identified attention on OAS1 as the antiviral activity was the most ANKFY1 and ZBTB42, which have not previously been robust (Figure 2A-C), basal OAS1 transcription is highly ascribed antiviral activity. We exogenously expressed IFN inducible (Figure 2D,E), the mRNA is readily detectable these ISGs in human A549 lung cells modified to express in infected patients (Figure 2F) and the locus encompasses ACE2 or modified to express both TMPRSS2 and ACE2 multiple SNPs that are associated with altered susceptibility and examined their ability to inhibit a 1st wave isolate of to infection and severe disease (Figure 2G). SARS-CoV-2 (CVR-GLA-1 (Rihn et al., 2021)).
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