Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still adapting to its new human host. Attention has focussed on the viral spike protein, but substantial variation has been seen in the ORF8 gene. Here, we show that SARS-CoV-2 ORF8 protein undergoes signal peptide-mediated processing through the endoplasmic reticulum and is secreted as a glycosylated, disulphide-linked dimer. The secreted protein from the prototype SARS-CoV-2 virus had no major effect on viability of a variety of cell types, or on IFN or NF-κB signalling. However, it modulated cytokine expression from primary CSF1-derived human macrophages, most notably by decreasing IL-6 and IL-8 secretion. Furthermore, a sequence polymorphism L84S that appeared early in the pandemic associated with the Clade S lineage of virus, showed a markedly different effect, of increasing IL-6 production. We conclude that ORF8 sequence polymorphisms can potentially affect SARS-CoV-2 virulence and should therefore be monitored in sequencing-based surveillance.
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Kriplani, N., Clohisey, S., Fonseca, S., Fletcher, S., Lee, H., Ashworth, J., Kurian, D., Lycett, S., Tait-Burkard, C., Baillie, J., Woolhouse, M., Carding, S., Stewart, J. & Digard, P. 2021, 'Secreted SARS-CoV-2 ORF8 modulates the cytokine expression profile of human macrophages', bioRxiv. https://doi.org/10.1101/2021.08.13.456266