A prenylated dsRNA sensor protects against severe COVID-19
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.
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