A Prenylated dsRNA Sensor Protects Against Severe COVID-19 and is Absent in Horseshoe Bats

Wickenhagen, A.; Sugrue, E.; Lytras, S.; Kuchi, S.; Turnbull, M. L.; Loney, C.; Herder, V.; Allan, J.; Jarmson, I.; Cameron-Ruiz, N.; Varjak, M.; Pinto, R. M.; Stewart, D. G.; Swingler, S.; Noerenberg, M.; Greenwood, E. J. D.; Crozier, T. W. M.; Gu, Q.; Clohisey, S.; Wang, B.; Trindade Maranhao Costa, F.; Freire Santana, M.; Carlos de Lima Ferreira, L.; ISARIC4C-Investigators,; Luiz Da Silva Filho, J.; Marti, M.; Stanton, R. J.; Wang, E. C. Y.; Castello-Palomares, A.; Ho, A.; Baillie, K.; Jarrett, R. F.; Robertson, D. L.; Palmarini, M.; Lehner, P. J.; Rihn, S. J.; Wilson, S. J.

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.