A prenylated dsRNA sensor protects against severe COVID-19
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal article |
| Language: | English |
| Published: |
American Association for the Advancement of Science
2021
|
| _version_ | 1797104627737427968 |
|---|---|
| author | Wickenhagen, A Sugrue, E Lytras, S Kuchi, S Noerenberg, M Turnbull, ML Loney, C Herder, V Allan, J Jarmson, I Cameron-Ruiz, N Varjak, M Pinto, RM Lee, JY Iselin, L Palmalux, N Stewart, DG Swingler, S Greenwood, EJD Crozier, TWM Gu, Q Davies, EL Clohisey, S Wang, B Trindade Maranhão Costa, F Freire Santana, M de Lima Ferreira, LC Murphy, L Fawkes, A Meynert, A Grimes, G Da Silva Filho, JL Marti, M Hughes, J Stanton, RJ Wang, ECY Ho, A Davis, I Jarrett, RF Castello, A Robertson, DL Semple, MG Openshaw, PJM Palmarini, M Lehner, PJ Baillie, JK Rihn, SJ Wilson, SJ |
| author2 | Mentzer, AJ |
| author_facet | Mentzer, AJ Wickenhagen, A Sugrue, E Lytras, S Kuchi, S Noerenberg, M Turnbull, ML Loney, C Herder, V Allan, J Jarmson, I Cameron-Ruiz, N Varjak, M Pinto, RM Lee, JY Iselin, L Palmalux, N Stewart, DG Swingler, S Greenwood, EJD Crozier, TWM Gu, Q Davies, EL Clohisey, S Wang, B Trindade Maranhão Costa, F Freire Santana, M de Lima Ferreira, LC Murphy, L Fawkes, A Meynert, A Grimes, G Da Silva Filho, JL Marti, M Hughes, J Stanton, RJ Wang, ECY Ho, A Davis, I Jarrett, RF Castello, A Robertson, DL Semple, MG Openshaw, PJM Palmarini, M Lehner, PJ Baillie, JK Rihn, SJ Wilson, SJ |
| author_sort | Wickenhagen, A |
| collection | OXFORD |
| description | 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.
|
| first_indexed | 2024-03-07T06:36:23Z |
| format | Journal article |
| id | oxford-uuid:f7cdde5f-bb2e-46e3-ab27-e5ddf950855a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:36:23Z |
| publishDate | 2021 |
| publisher | American Association for the Advancement of Science |
| record_format | dspace |
| spelling | oxford-uuid:f7cdde5f-bb2e-46e3-ab27-e5ddf950855a2022-03-27T12:45:36ZA prenylated dsRNA sensor protects against severe COVID-19Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f7cdde5f-bb2e-46e3-ab27-e5ddf950855aEnglishSymplectic ElementsAmerican Association for the Advancement of Science2021Wickenhagen, ASugrue, ELytras, SKuchi, SNoerenberg, MTurnbull, MLLoney, CHerder, VAllan, JJarmson, ICameron-Ruiz, NVarjak, MPinto, RMLee, JYIselin, LPalmalux, NStewart, DGSwingler, SGreenwood, EJDCrozier, TWMGu, QDavies, ELClohisey, SWang, BTrindade Maranhão Costa, FFreire Santana, Mde Lima Ferreira, LCMurphy, LFawkes, AMeynert, AGrimes, GDa Silva Filho, JLMarti, MHughes, JStanton, RJWang, ECYHo, ADavis, IJarrett, RFCastello, ARobertson, DLSemple, MGOpenshaw, PJMPalmarini, MLehner, PJBaillie, JKRihn, SJWilson, SJMentzer, AJISARIC4C InvestigatorsLee, JAngus, BINTRODUCTION 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. |
| spellingShingle | Wickenhagen, A Sugrue, E Lytras, S Kuchi, S Noerenberg, M Turnbull, ML Loney, C Herder, V Allan, J Jarmson, I Cameron-Ruiz, N Varjak, M Pinto, RM Lee, JY Iselin, L Palmalux, N Stewart, DG Swingler, S Greenwood, EJD Crozier, TWM Gu, Q Davies, EL Clohisey, S Wang, B Trindade Maranhão Costa, F Freire Santana, M de Lima Ferreira, LC Murphy, L Fawkes, A Meynert, A Grimes, G Da Silva Filho, JL Marti, M Hughes, J Stanton, RJ Wang, ECY Ho, A Davis, I Jarrett, RF Castello, A Robertson, DL Semple, MG Openshaw, PJM Palmarini, M Lehner, PJ Baillie, JK Rihn, SJ Wilson, SJ A prenylated dsRNA sensor protects against severe COVID-19 |
| title | A prenylated dsRNA sensor protects against severe COVID-19 |
| title_full | A prenylated dsRNA sensor protects against severe COVID-19 |
| title_fullStr | A prenylated dsRNA sensor protects against severe COVID-19 |
| title_full_unstemmed | A prenylated dsRNA sensor protects against severe COVID-19 |
| title_short | A prenylated dsRNA sensor protects against severe COVID-19 |
| title_sort | prenylated dsrna sensor protects against severe covid 19 |
| work_keys_str_mv | AT wickenhagena aprenylateddsrnasensorprotectsagainstseverecovid19 AT sugruee aprenylateddsrnasensorprotectsagainstseverecovid19 AT lytrass aprenylateddsrnasensorprotectsagainstseverecovid19 AT kuchis aprenylateddsrnasensorprotectsagainstseverecovid19 AT noerenbergm aprenylateddsrnasensorprotectsagainstseverecovid19 AT turnbullml aprenylateddsrnasensorprotectsagainstseverecovid19 AT loneyc aprenylateddsrnasensorprotectsagainstseverecovid19 AT herderv aprenylateddsrnasensorprotectsagainstseverecovid19 AT allanj aprenylateddsrnasensorprotectsagainstseverecovid19 AT jarmsoni aprenylateddsrnasensorprotectsagainstseverecovid19 AT cameronruizn aprenylateddsrnasensorprotectsagainstseverecovid19 AT varjakm aprenylateddsrnasensorprotectsagainstseverecovid19 AT pintorm aprenylateddsrnasensorprotectsagainstseverecovid19 AT leejy aprenylateddsrnasensorprotectsagainstseverecovid19 AT iselinl aprenylateddsrnasensorprotectsagainstseverecovid19 AT palmaluxn aprenylateddsrnasensorprotectsagainstseverecovid19 AT stewartdg aprenylateddsrnasensorprotectsagainstseverecovid19 AT swinglers aprenylateddsrnasensorprotectsagainstseverecovid19 AT greenwoodejd aprenylateddsrnasensorprotectsagainstseverecovid19 AT croziertwm aprenylateddsrnasensorprotectsagainstseverecovid19 AT guq aprenylateddsrnasensorprotectsagainstseverecovid19 AT daviesel aprenylateddsrnasensorprotectsagainstseverecovid19 AT clohiseys aprenylateddsrnasensorprotectsagainstseverecovid19 AT wangb aprenylateddsrnasensorprotectsagainstseverecovid19 AT trindademaranhaocostaf aprenylateddsrnasensorprotectsagainstseverecovid19 AT freiresantanam aprenylateddsrnasensorprotectsagainstseverecovid19 AT delimaferreiralc aprenylateddsrnasensorprotectsagainstseverecovid19 AT murphyl aprenylateddsrnasensorprotectsagainstseverecovid19 AT fawkesa aprenylateddsrnasensorprotectsagainstseverecovid19 AT meynerta aprenylateddsrnasensorprotectsagainstseverecovid19 AT grimesg aprenylateddsrnasensorprotectsagainstseverecovid19 AT dasilvafilhojl aprenylateddsrnasensorprotectsagainstseverecovid19 AT martim aprenylateddsrnasensorprotectsagainstseverecovid19 AT hughesj aprenylateddsrnasensorprotectsagainstseverecovid19 AT stantonrj aprenylateddsrnasensorprotectsagainstseverecovid19 AT wangecy aprenylateddsrnasensorprotectsagainstseverecovid19 AT hoa aprenylateddsrnasensorprotectsagainstseverecovid19 AT davisi aprenylateddsrnasensorprotectsagainstseverecovid19 AT jarrettrf aprenylateddsrnasensorprotectsagainstseverecovid19 AT castelloa aprenylateddsrnasensorprotectsagainstseverecovid19 AT robertsondl aprenylateddsrnasensorprotectsagainstseverecovid19 AT semplemg aprenylateddsrnasensorprotectsagainstseverecovid19 AT openshawpjm aprenylateddsrnasensorprotectsagainstseverecovid19 AT palmarinim aprenylateddsrnasensorprotectsagainstseverecovid19 AT lehnerpj aprenylateddsrnasensorprotectsagainstseverecovid19 AT bailliejk aprenylateddsrnasensorprotectsagainstseverecovid19 AT rihnsj aprenylateddsrnasensorprotectsagainstseverecovid19 AT wilsonsj aprenylateddsrnasensorprotectsagainstseverecovid19 AT wickenhagena prenylateddsrnasensorprotectsagainstseverecovid19 AT sugruee prenylateddsrnasensorprotectsagainstseverecovid19 AT lytrass prenylateddsrnasensorprotectsagainstseverecovid19 AT kuchis prenylateddsrnasensorprotectsagainstseverecovid19 AT noerenbergm prenylateddsrnasensorprotectsagainstseverecovid19 AT turnbullml prenylateddsrnasensorprotectsagainstseverecovid19 AT loneyc prenylateddsrnasensorprotectsagainstseverecovid19 AT herderv prenylateddsrnasensorprotectsagainstseverecovid19 AT allanj prenylateddsrnasensorprotectsagainstseverecovid19 AT jarmsoni prenylateddsrnasensorprotectsagainstseverecovid19 AT cameronruizn prenylateddsrnasensorprotectsagainstseverecovid19 AT varjakm prenylateddsrnasensorprotectsagainstseverecovid19 AT pintorm prenylateddsrnasensorprotectsagainstseverecovid19 AT leejy prenylateddsrnasensorprotectsagainstseverecovid19 AT iselinl prenylateddsrnasensorprotectsagainstseverecovid19 AT palmaluxn prenylateddsrnasensorprotectsagainstseverecovid19 AT stewartdg prenylateddsrnasensorprotectsagainstseverecovid19 AT swinglers prenylateddsrnasensorprotectsagainstseverecovid19 AT greenwoodejd prenylateddsrnasensorprotectsagainstseverecovid19 AT croziertwm prenylateddsrnasensorprotectsagainstseverecovid19 AT guq prenylateddsrnasensorprotectsagainstseverecovid19 AT daviesel prenylateddsrnasensorprotectsagainstseverecovid19 AT clohiseys prenylateddsrnasensorprotectsagainstseverecovid19 AT wangb prenylateddsrnasensorprotectsagainstseverecovid19 AT trindademaranhaocostaf prenylateddsrnasensorprotectsagainstseverecovid19 AT freiresantanam prenylateddsrnasensorprotectsagainstseverecovid19 AT delimaferreiralc prenylateddsrnasensorprotectsagainstseverecovid19 AT murphyl prenylateddsrnasensorprotectsagainstseverecovid19 AT fawkesa prenylateddsrnasensorprotectsagainstseverecovid19 AT meynerta prenylateddsrnasensorprotectsagainstseverecovid19 AT grimesg prenylateddsrnasensorprotectsagainstseverecovid19 AT dasilvafilhojl prenylateddsrnasensorprotectsagainstseverecovid19 AT martim prenylateddsrnasensorprotectsagainstseverecovid19 AT hughesj prenylateddsrnasensorprotectsagainstseverecovid19 AT stantonrj prenylateddsrnasensorprotectsagainstseverecovid19 AT wangecy prenylateddsrnasensorprotectsagainstseverecovid19 AT hoa prenylateddsrnasensorprotectsagainstseverecovid19 AT davisi prenylateddsrnasensorprotectsagainstseverecovid19 AT jarrettrf prenylateddsrnasensorprotectsagainstseverecovid19 AT castelloa prenylateddsrnasensorprotectsagainstseverecovid19 AT robertsondl prenylateddsrnasensorprotectsagainstseverecovid19 AT semplemg prenylateddsrnasensorprotectsagainstseverecovid19 AT openshawpjm prenylateddsrnasensorprotectsagainstseverecovid19 AT palmarinim prenylateddsrnasensorprotectsagainstseverecovid19 AT lehnerpj prenylateddsrnasensorprotectsagainstseverecovid19 AT bailliejk prenylateddsrnasensorprotectsagainstseverecovid19 AT rihnsj prenylateddsrnasensorprotectsagainstseverecovid19 AT wilsonsj prenylateddsrnasensorprotectsagainstseverecovid19 |