The P681H mutation in the spike glycoprotein of the alpha variant of SARS-CoV-2 escapes IFITM restriction and is necessary for type I interferon resistance

Lista, M. J. et al. (2022) The P681H mutation in the spike glycoprotein of the alpha variant of SARS-CoV-2 escapes IFITM restriction and is necessary for type I interferon resistance. Journal of Virology, 96(23), e0125022. (doi: 10.1128/jvi.01250-22) (PMID:36350154) (PMCID:PMC9749455)

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The appearance of new dominant variants of concern (VOC) of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) threatens the global response to the coronavirus disease 2019 (COVID-19) pandemic. Of these, the alpha variant (also known as B.1.1.7), which appeared initially in the United Kingdom, became the dominant variant in much of Europe and North America in the first half of 2021. The spike (S) glycoprotein of alpha acquired seven mutations and two deletions compared to the ancestral virus, including the P681H mutation adjacent to the polybasic cleavage site, which has been suggested to enhance S cleavage. Here, we show that the alpha spike protein confers a level of resistance to beta interferon (IFN-β) in human lung epithelial cells. This correlates with resistance to an entry restriction mediated by interferon-induced transmembrane protein 2 (IFITM2) and a pronounced infection enhancement by IFITM3. Furthermore, the P681H mutation is essential for resistance to IFN-β and context-dependent resistance to IFITMs in the alpha S. P681H reduces dependence on endosomal cathepsins, consistent with enhanced cell surface entry. However, reversion of H681 does not reduce cleaved spike incorporation into particles, indicating that it exerts its effect on entry and IFN-β downstream of furin cleavage. Overall, we suggest that, in addition to adaptive immune escape, mutations associated with VOC may well also confer a replication and/or transmission advantage through adaptation to resist innate immune mechanisms.

Item Type:Articles
Additional Information:This work was funded by Wellcome Trust Senior Research Fellowship WT098049AIA to S.J.D.N., MRC Project Grant MR/S000844/1 to S.J.D.N. and C.S., and funding from the Huo Family Foundation jointly to S.J.D.N., Katie Doores, Michael Malim, and Rocio Martinez Nunez. MR/S000844/1 is part of the EDCTP2 program supported by the European Union. H.W. is supported by the UK Medical Research Council (MR/N013700/ 1) and is a King’s College London member of the MRC Doctoral Training Partnership in Biomedical Sciences. This work is supported by the UKRI SARS-CoV-2 Genotype-2- Phenotype consortium. We also benefit from infrastructure support from the KCl Biomedical Research Centre, King’s Health Partners. Work at the CVR was also supported by the MRC MC_UU12014/2 and the Wellcome Trust (206369/Z/17/Z).
Glasgow Author(s) Enlighten ID:De Lorenzo, Dr Giuditta and Furnon, Dr Wilhelm and Suarez, Dr Nicolas and Cowton, Dr Vanessa and Palmarini, Professor Massimo and Patel, Professor Arvind and Orton, Dr Richard
Authors: Lista, M. J., Winstone, H., Wilson, H. D., Dyer, A., Pickering, S., Galao, R. P., De Lorenzo, G., Cowton, V. M., Furnon, W., Suarez, N., Orton, R., Palmarini, M., Patel, A. H., Snell, L., Nebbia, G., Swanson, C., and Neil, S. J. D.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:Journal of Virology
Publisher:American Society for Microbiology
ISSN (Online):1098-5514
Published Online:09 November 2022
Copyright Holders:Copyright © 2022 Lista et al.
First Published:First published in Journal of Virology 96(23):e0125022
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172630Basis of the host range and tissue tropism for hepatitis C virusArvind PatelMedical Research Council (MRC)MC_UU_12014/2III - Centre for Virus Research
301049Host determinants of disease outcomes in arboviral infectionsMassimo PalmariniWellcome Trust (WELLCOTR)206369/Z/17/ZIII - Centre for Virus Research