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"But Mouse, You Are Not Alone": On Some Severe Acute Respiratory Syndrome Coronavirus 2 Variants Infecting Mice
Michael J Kuiper1, Laurence O W Wilson2, Shruthi Mangalaganesh3,4
1CSIRO Data61, Dockands, Victoria, Australia.
Abstract:
In silico predictions combined with in vitro, in vivo, and in situ observations collectively suggest that mouse adaptation of the severe acute respiratory syndrome 2 virus requires an aromatic substitution in position 501 or position 498 (but not both) of the spike protein's receptor binding domain. This effect could be enhanced by mutations in positions 417, 484, and 493 (especially K417N, E484K, Q493K, and Q493R), and to a lesser extent by mutations in positions 486 and 499 (such as F486L and P499T). Such enhancements, due to more favorable binding interactions with residues on the complementary angiotensin-converting enzyme 2 interface, are, however, unlikely to sustain mouse infectivity on their own based on theoretical and experimental evidence to date. Our current understanding thus points to the Alpha, Beta, Gamma, and Omicron variants of concern infecting mice, whereas Delta and "Delta Plus" lack a similar biomolecular basis to do so. This paper identifies 11 countries (Brazil, Chile, Djibouti, Haiti, Malawi, Mozambique, Reunion, Suriname, Trinidad and Tobago, Uruguay, and Venezuela) where targeted local field surveillance of mice is encouraged because they may have come in contact with humans who had the virus with adaptive mutation(s). It also provides a systematic methodology to analyze the potential for other animal reservoirs and their likely locations.
Insights
Severe acute respiratory syndrome 2 virus adaptation in mice requires specific spike protein mutations. Alpha, Beta, Gamma, and Omicron variants may infect mice, unlike Delta variants.
Area of Science:
- Virology
- Molecular Biology
- Epidemiology
Background:
- The severe acute respiratory syndrome 2 (SARS-CoV-2) virus has demonstrated significant adaptability.
- Understanding viral adaptation mechanisms is crucial for predicting and controlling potential zoonotic transmissions.
Purpose of the Study:
- To investigate the molecular requirements for SARS-CoV-2 adaptation in mice.
- To identify specific mutations in the spike protein's receptor binding domain (RBD) that facilitate mouse adaptation.
- To assess the potential for different SARS-CoV-2 variants to infect mouse populations and identify at-risk regions for surveillance.
Main Methods:
- In silico prediction modeling.
- In vitro, in vivo, and in situ experimental observations.
- Analysis of spike protein mutations (e.g., at positions 417, 484, 493, 498, 499, 501) and their impact on angiotensin-converting enzyme 2 (ACE2) binding.
- Comparative analysis of SARS-CoV-2 variants (Alpha, Beta, Gamma, Delta, Omicron) for mouse infectivity potential.
Main Results:
- Mouse adaptation of SARS-CoV-2 necessitates aromatic substitution at position 501 or 498 in the spike protein RBD, but not both.
- Mutations K417N, E484K, Q493K, and Q493R significantly enhance binding interactions with mouse ACE2.
- Alpha, Beta, Gamma, and Omicron variants possess the necessary mutations for mouse adaptation, while Delta and Delta Plus variants do not.
- Eleven countries identified for targeted mouse surveillance due to potential human-virus contact with adaptive mutations.
Conclusions:
- Specific mutations in the SARS-CoV-2 spike protein RBD are critical for mouse adaptation.
- Certain variants (Alpha, Beta, Gamma, Omicron) are more likely to infect mice than others (Delta).
- Targeted surveillance in specific geographic regions is recommended to monitor potential SARS-CoV-2 reservoirs in mice and understand transmission dynamics.
