TY - JOUR AU - Kriplani, Nisha AU - Clohisey, Sara AU - Fonseca, Sonia AU - Fletcher, Sarah AU - Lee, Hui-Min AU - Ashworth, Jordan AU - Kurian, Dominic AU - Lycett, Samantha J. AU - Tait-Burkard, Christine AU - Baillie, J. Kenneth AU - Woolhouse, Mark E. J. AU - Carding, Simon R. AU - Stewart, James P. AU - Digard, Paul PY - 2021 DA - August TI - Secreted SARS-CoV-2 ORF8 modulates the cytokine expression profile of human macrophages JO - bioRxiv DO - https://doi.org/10.1101/2021.08.13.456266 AB - 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. PB - Cold Spring Harbor Laboratory Press UR - https://www.research.ed.ac.uk/en/publications/f7b29e13-c017-4b56-861c-28ac4a785f32 KW - Coronavirus (COVID-19) ER