Posts Tagged ‘OAS1’

Defective viral RNA sensing gene OAS1 linked to severe COVID-19

Reporter: Stephen J. Williams, Ph.D.

Source: https://www.science.org/doi/10.1126/science.abm3921

Defective viral RNA sensing linked to severe COVID-19

JOHN SCHOGGINS SCIENCE•28 Oct 2021•Vol 374, Issue 6567•pp. 535-536•DOI: 10.1126/science.abm39214,824

Why do some people with COVID-19 get sicker than others? Maybe exposure to a particularly high dose of the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), accounts for the difference. Perhaps deficiencies in diet, exercise, or sleep contribute to worse illness. Although many factors govern how sick people become, a key driver of the severity of COVID-19 appears to be genetic, which is common for other human viruses and infectious agents (1). On page 579 of this issue, Wickenhagen et al. (2) show that susceptibility to severe COVID-19 is associated with a single-nucleotide polymorphism (SNP) in the human gene 2′-5′-oligoadenylate synthetase 1 (OAS1).The authors reasoned that SARS-CoV-2 should be inhibited by interferon-mediated antiviral responses, which are among the first cellular defense mechanisms produced in response to a viral infection. Interferons are a group of cytokines that induce the transcription of a large cadre of genes, many of which encode proteins with the potential to directly inhibit the invading virus. Wickenhagen et al. interrogated many hundreds of these putative antiviral proteins for their ability to suppress SARS-CoV-2 in cultured cells and found that OAS1 was particularly potent against SARS-CoV-2.OAS1 is an enzyme that is activated in the presence of double-stranded RNA, which is scattered along an otherwise singlestranded SARS-CoV-2 genome because of an assortment of RNA hairpins and other secondary structures. Once activated, OAS1 catalyzes the polymerization of adenosine triphosphate (ATP) into a second messenger, 2′-5′-oligoadenylate. This then triggers the conversion of ribonuclease L (RNaseL) into its active form so that it can cleave viral RNA, effectively blunting viral replication (3). Wickenhagen et al. found that OAS1 is expressed in respiratory tissues of healthy donors and COVID-19 patients and that it interacts with a region of the SARS-CoV-2 genome that contains double-stranded RNA secondary structures (see the figure).OAS1 exists predominantly as two isoforms in humans—a longer isoform (p46) and a shorter version (p42). Genetic variation dictates which isoform will be expressed. In humans, p46 is expressed in people who have a SNP that causes alternative splicing of the OAS1 messenger RNA (mRNA). This results in the utilization of a terminal exon that is not used to translate p42. Thus, the carboxyl terminus of the p46 OAS1 protein contains a distinct four–amino acid motif that forms a prenylation site. Prenylation is a posttranslational modification that targets proteins to membranes. In cell culture experiments, Wickenhagen et al. showed that only OAS1 p46, but not p42, could inhibit SARS-CoV-2. However, when the prenylation site of p46 was engineered into p42, this chimeric p42 protein was able to inhibit SARS-CoV-2, which strongly implicates a role for OAS1 specifically at membranes.Why are membranes important? SARS-CoV-2, like all coronaviruses, co-opts cellular membranes at the endoplasmic reticulum to form double-membrane vesicles, in which the virus replicates its genome. Thus, membrane-bound OAS1 p46 may be specifically activated by RNA viruses that form membrane-bound vesicles for replication. Indeed, the unrelated cardiovirus A, which also forms vesicular membranous structures, was inhibited by OAS1. Conversely, other respiratory RNA viruses, such as human parainfluenza virus type 3 and human respiratory syncytial virus, which do not use membrane-tethered vesicles for replication, were not inhibited by p46.Wickenhagen et al. examined a cohort of 499 COVID-19 patients hospitalized in the UK. Whereas all patients expressed OAS1, 42.5% of them did not express the antiviral p46 isoform. These patients were statistically more likely to have severe COVID-19 (be admitted to the intensive care unit). This suggests that OAS1 is an important antiviral factor in the control of SARS-CoV-2 infection and that its inability to activate RNaseL results in prolonged infections and severe disease, although other factors likely contribute. The authors also examined animals known to harbor different coronaviruses. They found evidence for prenylated OAS1 proteins in mice, cows, and camels. Notably, horseshoe bats, which are considered a possible reservoir for SARS-related coronaviruses (4), lack a prenylation motif in their OAS1 because of genomic changes that eliminated the critical four-amino acid motif. A horseshoe bat (Rhinolophus ferrumequinum) OAS1 was unable to inhibit SARS-CoV-2 infection in cell culture. Conversely, the black flying fox (Pteropus alecto)—a pteropid bat that is a reservoir for the Nipah and Hendra viruses, which can also infect humans—possesses a prenylated OAS1 that can inhibit SARS-CoV-2. These findings indicate that horseshoe bats may be genetically and evolutionarily primed to be optimal reservoir hosts for certain coronaviruses, like SARS-CoV-2.Other studies have now shown that the p46 OAS1 variant, which resides in a genomic locus inherited from Neanderthals (57), correlates with protection from COVID-19 severity in various populations (89). These findings mirror previous studies indicating that outcomes with West Nile virus (10) and hepatitis C virus (11) infection, both of which also use membrane vesicles for replication, are also associated with genetic variation at the human OAS1 locus. Another elegant functional study complements the findings of Wickenhagen et al. by also demonstrating that prenylated OAS1 inhibits multiple viruses, including SARS-CoV-2, and is associated with protection from severe COVID-19 in patients (12).There is a growing body of evidence that provides critical understanding of how human genetic variation shapes the outcome of infectious diseases like COVID-19. In addition to OAS1, genetic variation in another viral RNA sensor, Toll-like receptor 7 (TLR7), is associated with severe COVID-19 (1315). The effects appear to be exclusive to males, because TLR7 is on the X chromosome, so inherited deleterious mutations in TLR7 therefore result in immune cells that fail to produce normal amounts of interferon, which correlates with more severe COVID-19. Our knowledge of the host cellular factors that control SARS-CoV-2 is rapidly increasing. These findings will undoubtedly open new avenues into SARS-CoV-2 antiviral immunity and may also be beneficial for the development of strategies to treat or prevent severe COVID-19.

References and Notes

1J. L. Casanova, Proc. Natl. Acad. Sci. U.S.A.112, E7118 (2015).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR2A. Wickenhagen et al., Science374, eabj3624 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR3H. Kristiansen, H. H. Gad, S. Eskildsen-Larsen, P. Despres, R. Hartmann, J. Interferon Cytokine Res.31, 41 (2011).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR4S. Lytras, W. Xia, J. Hughes, X. Jiang, D. L. Robertson, Science373, 968 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR5S. Zhou et al., Nat. Med.27, 659 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR6H. Zeberg, S. Pääbo, Proc. Natl. Acad. Sci. U.S.A.118, e2026309118 (2021).CROSSREFPUBMEDGOOGLE SCHOLAR7F. L. Mendez, J. C. Watkins, M. F. Hammer, Mol. Biol. Evol.30, 798 (2013).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR8A. R. Banday et al., medRxiv2021).GO TO REFERENCECROSSREFGOOGLE SCHOLAR9E. Pairo-Castineira et al., Nature591, 92 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR10J. K. Lim et al., PLOS Pathog.5, e1000321 (2009).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR11M. K. El Awady et al., J. Gastroenterol. Hepatol.26, 843 (2011).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR12F. W. Soveg et al., eLife10, e71047 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR13T. Asano et al., Sci. Immunol.6, eabl4348 (2021).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR14C. Fallerini et al., eLife10, e67569 (2021).CROSSREFPUBMEDGOOGLE SCHOLAR15C. I. van der Made et al., JAMA324, 663 (2020).GO TO REFERENCECROSSREFPUBMEDGOOGLE SCHOLAR

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