Q493K and Q498H substitutions in Spike promote adaptation of SARS-CoV-2 in mice
Open accessAbstract
BACKGROUND: An ideal animal model to study SARS-coronavirus 2 (SARS-CoV-2) pathogenesis and evaluate therapies and vaccines should reproduce SARS-CoV-2 infection and recapitulate lung disease like those seen in humans. The angiotensin-converting enzyme 2 (ACE2) is a functional receptor for SARS-CoV-2, but mice are resistant to the infection because their ACE2 is incompatible with the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein . METHODS: SARS-CoV-2 was passaged in BALB/c mice to obtain mouse-adapted virus strain. Complete genome deep sequencing of different generations of viruses was performed to characterize the dynamics of the adaptive mutations in SARS-CoV-2. Indirect immunofluorescence analysis and Biolayer interferometry experiments determined the binding affinity of mouse-adapted SARS-CoV-2 WBP-1 RBD to mouse ACE2 and human ACE2. Finally, we tested whether TLR7/8 agonist Resiquimod (R848) could also inhibit the replication of WBP-1 in the mouse model. FINDINGS: The mouse-adapted strain WBP-1 showed increased infectivity in BALB/c mice and led to severe interstitial pneumonia. We characterized the dynamics of the adaptive mutations in SARS-CoV-2 and demonstrated that Q493K and Q498H in RBD significantly increased its binding affinity towards mouse ACE2. Additionally, the study tentatively found that the TLR7/8 agonist Resiquimod was able to protect mice against WBP-1 challenge. Therefore, this mouse-adapted strain is a useful tool to investigate COVID-19 and develop new therapies. INTERPRETATION: We found for the first time that the Q493K and Q498H mutations in the RBD of WBP-1 enhanced its interactive affinities with mACE2. The mouse-adapted SARS-CoV-2 provides a valuable tool for the evaluation of novel antiviral and vaccine strategies. This study also tentatively verified the antiviral activity of TLR7/8 agonist Resiquimod against SARS-CoV-2 in vitro and in vivo. FUNDING: This research was funded by the National Key Research and Development Program of China (2020YFC0845600) and Emergency Science and Technology Project of Hubei Province (2020FCA046) and Robert A. Welch Foundation (C-1565).
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Efficient usage of murine ACE2 by the Omicron spike is in keeping with the presence of mutations K417N and N501Y, which can emerge upon SARS-CoV-2 adaptation to experimentally infected mice.
“The efficient usage of murine ACE2 is in keeping with the presence of the mutations K417N and N501Y, which can also emerge upon SARS-CoV-2 adaptation to experimentally infected mice”
From The Omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic (2022) · cites this paper as Huang et al., 2021
The Omicron spike harbors mutations Q493R and Q498R, which are related to exchanges Q493K and Q498H detected in mouse-adapted SARS-CoV-2.
“In addition, the Omicron spike harbors mutations Q493R and Q498R, which are related to exchanges Q493K and Q498H, which were also detected in mouse-adapted SARS-CoV-2”
From The Omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic (2022) · cites this paper as Huang et al., 2021
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- Authors
- Huang, K., Zhang, Y., Hui, X., Zhao, Y., Gong, W., Wang, T., Zhang, S., Yang, Y., Deng, F., Zhang, Q., Chen, X., Yang, Y., Sun, X., Chen, H., Tao, Y. J., Zou, Z., & Jin, M.
- Affiliations
- Huazhong Agricultural University (CN)
- Rice University (US)
- Corresponding author
- Zou, Zhong
- Jin, Meilin
- ORCID
- Venue
- EBioMedicine
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 67
- Pages
- 103381
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC8118724
- OpenAlex
- W3162133013
- Cited by
- 119
- References
- 52
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 20 · 2023: 17 · 2022: 55 · 2021: 14
- FWCI
- 8.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Rice Research Repository (Rice University) (submittedVersion, cc-by-nc-nd)
- Funders
- Welch Foundation (C-1565)
- Chinese Academy of Sciences
- Hubei Province Department of Science and Technology (2020FCA046)
- State Key Laboratory of Virology
- National Key Research and Development Program of China (2020YFC0845600)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- SARS-CoV-2, spike protein, receptor binding domain, mouse-adapted virus, ACE2 receptor, receptor binding affinity, interstitial lung disease, TLR7/8 agonist, resiquimod, antiviral activity, adaptive mutation
- MeSH terms
- Whole Genome Sequencing, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Adaptation, Physiological, Animals, Binding Sites, Chlorocebus aethiops, Disease Models, Animal, Female, Humans, Imidazoles, Mice, Inbred BALB C, Serial Passage, Vero Cells, Virus Replication, Caco-2 Cells, Amino Acid Substitution, Mice, High-Throughput Nucleotide Sequencing, Spike Glycoprotein, Coronavirus
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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