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bioRxiv · 10.1101/2021.12.16.473063

Passage of SARS-CoV-2 in cells expressing human and mouse ACE2 selects for mouse-adapted and ACE2-independent viruses

Yan, K.·Dumenil, T.·Le, T. T.·Tang, B.·Bishop, C.·Suhrbier, A.·Rawle, D. J.
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Abstract

Human ACE2 (hACE2) is the key cell attachment and entry receptor for SARS-CoV-2, with the original SARS-CoV-2 isolates unable to use mouse ACE2 (mACE2). Herein we describe a new system for generating mouse-adapted SARS-CoV-2 in vitro by serial passaging virus in co-cultures of cell lines expressing hACE2 and mACE2. Mouse-adapted viruses emerged with up to five amino acid changes in the spike protein, all of which have been seen in human isolates. Mouse-adapted viruses replicated to high titers in C57BL/6J mouse lungs and nasal turbinates, and caused severe lung histopathology. One mouse-adapted virus was also able to replicate efficiently in ACE2-negative cell lines, with ACE2-independent entry by SARS-CoV-2 representing a new biology for SARS-CoV-2 that has potential widespread implications for disease and intervention development.

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Yan, K., Dumenil, T., Le, T. T., Tang, B., Bishop, C., Suhrbier, A., Rawle, D. J.. 2021-12-21. Passage of SARS-CoV-2 in cells expressing human and mouse ACE2 selects for mouse-adapted and ACE2-independent viruses. https://doi.org/10.1101/2021.12.16.473063

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