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Journal Articles Science Year : 2021

A prenylated dsRNA sensor protects against severe COVID-19

Elena Sugrue
Spyros Lytras
Srikeerthana Kuchi
  • Function : Author
Marko Noerenberg
Matthew Turnbull
Colin Loney
Vanessa Herder
Jay Allan
  • Function : Author
Innes Jarmson
  • Function : Author
Natalia Cameron-Ruiz
Margus Varjak
Rute Pinto
Jeffrey Lee
Louisa Iselin
  • Function : Author
Natasha Palmalux
Douglas Stewart
  • Function : Author
Simon Swingler
Edward Greenwood
Thomas Crozier
Quan Gu
Emma Davies
Sara Clohisey
Bo Wang
Fabio Trindade Maranhão Costa
Monique Freire Santana
Luiz Carlos de Lima Ferreira
Lee Murphy
Angie Fawkes
Alison Meynert
Graeme Grimes
Joao Luiz da Silva Filho
  • Function : Author
Matthias Marti
Joseph Hughes
Richard Stanton
Eddie Wang
Antonia Ho
  • Function : Author
Ilan Davis
Ruth Jarrett
Alfredo Castello
David Robertson
Malcolm Semple
Peter Openshaw
Massimo Palmarini
Paul Lehner
J Kenneth Baillie
  • Function : Author
Suzannah Rihn
Sam Wilson
J. Kenneth Baillie


INTRODUCTION Interferons (IFNs) are cytokines that are rapidly deployed in response to invading pathogens. By initiating a signaling cascade that stimulates the expression of hundreds of genes, IFNs create an antiviral state in host cells. Because IFNs heavily influence COVID-19 outcomes, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication can be inhibited by the antiviral state, it is important to understand how the individual antiviral effectors encoded by IFN-stimulated genes (ISGs) inhibit SARS-CoV-2. RATIONALE We hypothesized that IFN-stimulated antiviral effectors can inhibit SARS-CoV-2, and that variation at the loci encoding these defenses underlies why some people are more susceptible to severe COVID-19. RESULTS We used arrayed ISG expression screening to reveal that 2′-5′-oligoadenylate synthetase 1 (OAS1) consistently inhibited SARS-CoV-2 in different contexts. Using CRISPR-Cas9, we found that endogenous OAS1 makes a substantial contribution to the antiviral state by recognizing short stretches of double-stranded RNA (dsRNA) and activating RNase L. We globally mapped where OAS1 binds to SARS-CoV-2 viral RNAs and found that OAS1 binding is remarkably specific, with two conserved stem loops in the SARS-CoV-2 5′-untranslated region (UTR) constituting the principal viral target. OAS1 expression was readily detectable at the sites of infection in individuals who died of COVID-19, and specific OAS1 alleles are known to be associated with altered susceptibility to infection and severe disease. It had previously been reported that alleles containing a common splice-acceptor single nucleotide polymorphism in OAS1 (Rs10774671) were associated with less severe COVID-19. We determined that people with at least one allele with a G at this position could express a prenylated form of OAS1 (p46), whereas other individuals could not. Using a series of mutants, we found that C-terminal prenylation was necessary for OAS1 to initiate a block to SARS-CoV-2. Furthermore, confocal microscopy revealed that prenylation targeted OAS1 to perinuclear structures rich in viral dsRNA, whereas non-prenylated OAS1 was diffusely localized and unable to initiate a detectable block to SARS-CoV-2 replication. The realization that prenylation is essential for OAS1-mediated sensing of SARS-CoV-2 allowed us to examine the transcriptome of infected patients and investigate whether there was a link between the expression of prenylated OAS1 and SARS-CoV-2 disease progression. Analysis of the OAS1 transcripts from 499 hospitalized COVID-19 patients revealed that expressing prenylated OAS1 was associated with protection from severe COVID-19. Because prenylated OAS1 was so important in human cases, we wanted to determine whether horseshoe bats, the likely source of SARS-CoV-2, possessed the same defense. When we examined the genomic region where the prenylation signal should reside, retrotransposition of a long terminal repeat sequence had ablated this signal, preventing the expression of prenylated anti-CoV OAS1 in these bats. CONCLUSION C-terminal prenylation targets OAS1 to intracellular sites rich in viral dsRNA, which are likely the SARS-CoV-2 replicative organelles. Once in the right place, OAS1 binds to dsRNA structures in the SARS-CoV-2 5′-UTR and initiates a potent block to SARS-CoV-2 replication. Thus, the correct targeting of OAS1 and the subsequent inhibition of SARS-CoV-2 likely underpins the genetic association of alleles containing a G at Rs10774671 with reduced susceptibility to infection and severe disease in COVID-19. Moreover, the conspicuous absence of this antiviral defense in horseshoe bats potentially explains why SARS-CoV-2 is so sensitive to this defense in humans.

Dates and versions

hal-03451263 , version 1 (26-11-2021)



Marc-Emmanuel Dumas, Arthur Wickenhagen, Elena Sugrue, Spyros Lytras, Srikeerthana Kuchi, et al.. A prenylated dsRNA sensor protects against severe COVID-19. Science, 2021, 374 (6567), pp.eabj3624. ⟨10.1126/science.abj3624⟩. ⟨hal-03451263⟩


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