A Prenylated dsRNA Sensor Protects Against Severe COVID-19 and is Absent in Horseshoe Bats
Matthew L Turnbull,
Rute M Pinto,
Douglas G Stewart,
Edward J D Greenwood,
Thomas W M Crozier,
Fabio Trindade Maranhao Costa,
Monique Freire Santana,
Luiz Carlos de Lima Ferreira,
Joao Luiz Da Silva Filho,
Richard James Stanton,
Eddie C Y Wang,
Ruth F Jarrett,
David L Robertson,
Paul J. Lehner,
Suzannah J Rihn,
Sam J Wilson
Posted 09 May 2021
medRxiv DOI: 10.1101/2021.05.05.21256681
Posted 09 May 2021
Cell autonomous antiviral defenses can inhibit the replication of viruses and reduce transmission and disease severity. To better understand the antiviral response to SARS-CoV-2, we used interferon-stimulated gene (ISG) expression screening to reveal that OAS1, through RNase L, potently inhibits SARS-CoV-2. We show that while some people can express a prenylated OAS1 variant, that is membrane-associated and blocks SARS-CoV-2 infection, other people express a cytosolic, nonprenylated OAS1 variant which does not detect SARS-CoV-2 (determined by the splice-acceptor SNP Rs10774671). Alleles encoding nonprenylated OAS1 predominate except in people of African descent. Importantly, in hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting this antiviral defense is a major component of a protective antiviral response. Remarkably, approximately 55 million years ago, retrotransposition ablated the OAS1 prenylation signal in horseshoe bats (the presumed source of SARS-CoV-2). Thus, SARS-CoV-2 never had to adapt to evade this defense. As prenylated OAS1 is widespread in animals, the billions of people that lack a prenylated OAS1 could make humans particularly vulnerable to the spillover of coronaviruses from horseshoe bats.
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