Adaptation of SARS-CoV-2 to ACE2 H353K mice reveals new spike residues that drive mouse infection

Kun Li; Abhishek Verma; Pengfei Li; Miguel E Ortiz; Grant M Hawkins; Nicholas J Schnicker; Peter J Szachowicz; Alejandro Pezullo; Christine L Wohlford-Lenane; Tom Kicmal; David K Meyerholz; Tom Gallagher; Stanley Perlman; Paul B McCray Jr

doi:10.1128/jvi.01510-23

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Adaptation of SARS-CoV-2 to ACE2 H353K mice reveals new spike residues that drive mouse infection

Journal article

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Peer reviewed

Adaptation of SARS-CoV-2 to ACE2 H353K mice reveals new spike residues that drive mouse infection

Kun Li, Abhishek Verma, Pengfei Li, Miguel E Ortiz, Grant M Hawkins, Nicholas J Schnicker, Peter J Szachowicz, Alejandro Pezullo, Christine L Wohlford-Lenane, Tom Kicmal, …

Journal of virology, Vol.98(1), e0151023

01/23/2024

DOI: 10.1128/jvi.01510-23

PMCID: PMC10804960

PMID: 38168680

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10804960View

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Abstract

We developed a new mouse model with a humanized angiotensin converting enzyme 2 (ACE2) locus that preserves native regulatory elements. A single point mutation in mouse ACE2 (H353K) was sufficient to confer infection with ancestral severe acute respiratory syndrome-coronavirus-2 virus. Through serial passage, a virulent mouse-adapted strain was obtained. In aged mACE2H353K mice, the mouse-adapted strain caused diffuse alveolar disease. The mouse-adapted virus also infected standard BALB/c and C57BL/6 mice, causing severe disease. The mouse-adapted virus acquired five new missense mutations including two in spike (K417E, Q493K), one each in nsp4, nsp9, and M and a single nucleotide change in the 5' untranslated region. The Q493K spike mutation arose early in serial passage and is predicted to provide affinity-enhancing molecular interactions with mACE2 and further increase the stability and affinity to the receptor. This new model and mouse-adapted virus will be useful to evaluate COVID-19 disease and prophylactic and therapeutic interventions.

Pathogenesis

SARS-CoV-2

coronavirus

mouse-adapted virus

Details

Title: Subtitle: Adaptation of SARS-CoV-2 to ACE2 H353K mice reveals new spike residues that drive mouse infection
Creators: Kun Li - University of Iowa
Abhishek Verma - University of Iowa
Pengfei Li - University of Iowa
Miguel E Ortiz - Department of Pediatrics, The University of Iowa, Iowa City, Iowa, USA
Grant M Hawkins - Loyola University Chicago
Nicholas J Schnicker - University of Iowa
Peter J Szachowicz - University of Iowa
Alejandro Pezullo - University of Iowa
Christine L Wohlford-Lenane - University of Iowa
Tom Kicmal - Loyola University Chicago
David K Meyerholz - University of Iowa
Tom Gallagher - Loyola University Chicago
Stanley Perlman - Department of Microbiology and Immunology, The University of Iowa, Iowa City, Iowa, USA
Paul B McCray Jr - Department of Microbiology and Immunology, The University of Iowa, Iowa City, Iowa, USA
Resource Type: Journal article
Publication Details: Journal of virology, Vol.98(1), e0151023
DOI: 10.1128/jvi.01510-23
PMID: 38168680
PMCID: PMC10804960
NLM abbreviation: J Virol
eISSN: 1098-5514
Grant note: name: HHS | National Institutes of Health, award: P01 AI060699; name: HHS | National Institutes of Health, award: R01 AI129269
Language: English
Electronic publication date: 01/03/2024
Date published: 01/23/2024
Academic Unit: Molecular Physiology and Biophysics; Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Infectious Disease (Pediatrics); Internal Medicine
Record Identifier: 9984539658502771

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