Natural evolution of SARS-CoV-2 variants in K18-ACE2 mice gives rise to more virulent virus and variant alleles associated with treatment resistance.

Willett, J. D. S.; Gravel, A.; Dubuc, I.; Gudimard, L.; Fortin, P.; Liu, J.-L.; Galvez, J. H.; Zwaig, M.; Roy, A.-M.; Lee, S.; Chen, S.-H.; Ragoussis, I.; Flamand, L.

doi:10.1101/2023.01.16.523994

bioRxiv · 10.1101/2023.01.16.523994

Natural evolution of SARS-CoV-2 variants in K18-ACE2 mice gives rise to more virulent virus and variant alleles associated with treatment resistance.

Willett, J. D. S.·Gravel, A.·Dubuc, I.·Gudimard, L.·Fortin, P.·Liu, J.-L.·Galvez, J. H.·Zwaig, M.·Roy, A.-M.·Lee, S.·Chen, S.-H.·Ragoussis, I.·Flamand, L.

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Abstract

The persistence of COVID-19 is partly due to viral evolution reducing vaccine and treatment efficacy. Serial infections of Wuhan-like SARS-CoV-2 in Balb/c mice yielded mouse-adapted strains with greater infectivity and mortality. We investigated if passaging unmodified B.1.351 (Beta) and B.1.617.2 (Delta) 20 times in K18-ACE2 mice, expressing human ACE2 receptor, in a BSL-3 laboratory without selective pressures, would drive human health-relevant evolution and if evolution was lineage-dependent. Late-passage virus caused more severe disease, at organism and lung tissue scales, with late-passage Delta demonstrating antibody resistance and interferon suppression. This resistance co-occurred with a de novo spike S371F mutation, linked with both traits. S371F, an Omicron-characteristic mutation, was co-inherited at times with spike E1182G per Nanopore sequencing, existing in different quasi-species at others. Both are linked to mammalian GOLGA7 and ZDHHC5 interactions, which mediate viral-cell entry and antiviral response. This study demonstrates SARS-CoV-2s tendency to evolve with phenotypic consequences, its evolution varying by lineage, and suggests non-dominant quasi-species contribute.

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Willett, J. D. S., Gravel, A., Dubuc, I., Gudimard, L., Fortin, P., Liu, J.-L., Galvez, J. H., Zwaig, M., Roy, A.-M., Lee, S., Chen, S.-H., Ragoussis, I., Flamand, L.. 2023-01-17. Natural evolution of SARS-CoV-2 variants in K18-ACE2 mice gives rise to more virulent virus and variant alleles associated with treatment resistance.. https://doi.org/10.1101/2023.01.16.523994

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