Alternative splicing of <i>OAS1</i> alters the risk for severe COVID-19

Huffman, Jennifer E.; Butler‐Laporte, Guillaume; Khan, Atlas; Drivas, Theodore G.; Peloso, Gina M.; Nakanishi, Teruyuki; Verma, Anurag; Kiryluk, Krzysztof; Richards, J. Brent; Zeberg, Hugo

doi:10.1101/2021.03.20.21254005

Cited by 15 publications

(16 citation statements)

References 20 publications

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“…A different Neanderthal haplotype block, at the OAS1-OAS3 cluster, is protective against severe COVID-19 in Eurasians [117][118][119] , producing an OAS1 splice form with higher enzymatic activity 128 . The ancestral variant, still present in Africans, appears to confer a similar magnitude of protection against severe COVID-19, underscoring the value of the reintroduction 129 .…”

Section: The Continuous Evolution Of Immune Variationmentioning

confidence: 85%

Human immune diversity: from evolution to modernity

et al. 2021

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Section: The Continuous Evolution Of Immune Variationmentioning

confidence: 85%

Human immune diversity: from evolution to modernity

et al. 2021

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“…Our evaluation of OAS1 antiviral activity in vitro, combined with our analysis of OAS1 transcripts in patient cohorts, indicates that the protective Neanderthal OAS1 haplotype ( 22 , 24 ) likely prevents severe disease through specifying the expression of prenylated OAS1, which directs dsRNA sensing to the sites of SARS-CoV-2 replication. Indeed, through combining multiple studies, Huffman et al , also concluded that the Rs10774671 SNP is responsible for the protection conferred by the Neanderthal haplotype ( 59 ).…”

Section: Prenylated Oas1 Is Associated With Less Severe Covid-19mentioning

confidence: 99%

A prenylated dsRNA sensor protects against severe COVID-19

Wickenhagen

Sugrue

Lytras

et al. 2021

Science

176

145

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The bat connection The heterogeneity of COVID-19 makes it challenging to predict the course of infection in an individual. Upon virus infection, interferons (IFNs) generate the initial signals for cellular defenses. Knowing that defects in IFN signaling are associated with more severe COVID-19, Wickenhagen et al . used IFN-stimulated gene expression screening on human lung cells from which they identified a gene for 2′-5′-oligoadenylate synthetase 1 (OAS1) (see the Perspective by Schoggins). OAS1 stimulates RNase L to inhibit the virus with a surprising degree of specificity, targeting the membranous organelles in which it replicates. In most mammals, OAS1 is attached to membranes by a prenyl group. However, billions of humans do not have the prenylated OAS1 haplotype, including many experiencing severe COVID-19. The same is true for horseshoe bats, prolific sources of betacoronaviruses, because of an ancient retrotransposition event. —CA

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“…A study has shown that a major genetic risk factor for severe COVID-19 is linked to the Neanderthal genome 16 . A single point mutation in the OAS1 gene affecting splicing, and possibly OAS1 levels, has been identified [17][18][19] . To follow up on these studies, we investigated whether patients carrying this mutation had a different disease outcome and possibly a unique transcriptome signature.…”

Section: Longitudinal Analysis Of the Immune Transcriptomes While Hos...mentioning

confidence: 99%

Immune transcriptome analysis of COVID-19 patients infected with SARS-CoV-2 variants carrying the E484K escape mutation identifies a distinct gene module

Lee

Knabl²,

Wieser³

et al. 2022

Sci Rep

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Fast-spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) energize the COVID-19 pandemic. While viral infections elicit a conserved immune response, it is not known whether SARS-CoV-2 variants, which display enhanced binding to the ACE2 receptor and reduced neutralizing activity by vaccine-elicited antibodies, prompt specific genomic immune responses. To test this, we generated and investigated the transcriptomes in BCs from hospitalized patients infected with either the Alpha variant (n = 36) or with the Alpha variant that had acquired the E484K escape mutation (Alpha+E484K) (n = 13). We identified a gene module preferentially activated in patients infected with the Alpha+E484K variant and in patients infected with the Beta (n = 9) and Gamma (n = 3) variants that also carry by the E484K escape mutation. The E484K signature was enriched for genes preferentially expressed in monocytes and linked to severe viral infection. However, both cohorts had undergone similar treatments and no differences in disease severity were reported suggesting that this signature reflects a variant response and does not necessarily associate with disease outcome. Additionally, longitudinal transcriptome analyses revealed a more persistent retention of immune signatures in Alpha+E484K patients throughout the entire course of COVID-19 disease and convalescence. While the OAS1 Neanderthal mutation has been linked to a milder COVID-19 pathology, we did not identify significant immune transcriptomes differences in the 25 patients homozygous for this mutation. Our study offers insights into distinct molecular immune responses elicited by SARS-CoV-2 variants carrying the E484K escape mutation throughout the COVID-19 disease.

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Alternative splicing of OAS1 alters the risk for severe COVID-19

Cited by 15 publications

References 20 publications

Human immune diversity: from evolution to modernity

Human immune diversity: from evolution to modernity

A prenylated dsRNA sensor protects against severe COVID-19

Immune transcriptome analysis of COVID-19 patients infected with SARS-CoV-2 variants carrying the E484K escape mutation identifies a distinct gene module

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