Secreted SARS-CoV-2 ORF8 modulates the cytokine expression profile of human macrophages

Kriplani, N.; Clohisey, S. M. R.; Fonseca, S.; Fletcher, S.; Lee, H.-M.; Ashworth, J.; Kurian, D.; Lycett, S. J.; Tait-Burkard, C.; Baillie, J. K.; Woolhouse, M. E. J.; Carding, S. R.; Stewart, J. P.; Digard, P.

doi:10.1101/2021.08.13.456266

bioRxiv · 10.1101/2021.08.13.456266

Secreted SARS-CoV-2 ORF8 modulates the cytokine expression profile of human macrophages

Kriplani, N.·Clohisey, S. M. R.·Fonseca, S.·Fletcher, S.·Lee, H.-M.·Ashworth, J.·Kurian, D.·Lycett, S. J.·Tait-Burkard, C.·Baillie, J. K.·Woolhouse, M. E. J.·Carding, S. R.·Stewart, J. P.·Digard, P.

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Abstract

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-{kappa}B 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. M. R., Fonseca, S., Fletcher, S., Lee, H.-M., Ashworth, J., Kurian, D., Lycett, S. J., Tait-Burkard, C., Baillie, J. K., Woolhouse, M. E. J., Carding, S. R., Stewart, J. P., Digard, P.. 2021-08-13. Secreted SARS-CoV-2 ORF8 modulates the cytokine expression profile of human macrophages. https://doi.org/10.1101/2021.08.13.456266

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