The P681H mutation in the Spike glycoprotein confers Type I interferon resistance in the SARS-CoV-2 alpha (B.1.1.7) variant

Lista, M. J.; Winstone, H.; Wilson, H.; Dyer, A.; Pickering, S.; Galao, R. P.; De Lorenzo, G.; Cowton, V.; Furnon, W.; Suarez, N. M.; Orton, R.; Palmarini, M.; Patel, A. H.; Snell, L. B.; Nebbia, G.; Swanson, C. M.; Neil, S.

doi:10.1101/2021.11.09.467693

bioRxiv · 10.1101/2021.11.09.467693

The P681H mutation in the Spike glycoprotein confers Type I interferon resistance in the SARS-CoV-2 alpha (B.1.1.7) variant

Lista, M. J.·Winstone, H.·Wilson, H.·Dyer, A.·Pickering, S.·Galao, R. P.·De Lorenzo, G.·Cowton, V.·Furnon, W.·Suarez, N. M.·Orton, R.·Palmarini, M.·Patel, A. H.·Snell, L. B.·Nebbia, G.·Swanson, C. M.·Neil, S.

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Abstract

Variants of concern (VOCs) of severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) threaten the global response to the COVID-19 pandemic. The alpha (B.1.1.7) variant appeared in the UK became dominant in Europe and North America in early 2021. The Spike glycoprotein of alpha has acquired a number mutations including the P681H mutation in the polybasic cleavage site that has been suggested to enhance Spike cleavage. Here, we show that the alpha Spike protein confers a level of resistance to the effects of interferon-{beta} (IFN{beta}) in lung epithelial cells. This correlates with resistance to restriction mediated by interferon-induced transmembrane protein-2 (IFITM2) and a pronounced infection enhancement by IFITM3. Furthermore, the P681H mutation is necessary for comparative resistance to IFN{beta} in a molecularly cloned SARS-CoV-2 encoding alpha Spike. Overall, we suggest that in addition to adaptive immune escape, mutations associated with VOCs also confer replication advantage through adaptation to resist innate immunity.

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Lista, M. J., Winstone, H., Wilson, H., Dyer, A., Pickering, S., Galao, R. P., De Lorenzo, G., Cowton, V., Furnon, W., Suarez, N. M., Orton, R., Palmarini, M., Patel, A. H., Snell, L. B., Nebbia, G., Swanson, C. M., Neil, S.. 2021-11-10. The P681H mutation in the Spike glycoprotein confers Type I interferon resistance in the SARS-CoV-2 alpha (B.1.1.7) variant. https://doi.org/10.1101/2021.11.09.467693

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