"But Mouse, You Are Not Alone": On Some Severe Acute Respiratory Syndrome Coronavirus 2 Variants Infecting Mice

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.

Keywords: AlphaFold; in silico; in vitro; in vivo; COVID-19; SARS-CoV-2; animal reservoir; mouse adaptation; variants.

Figure 1

The RBD/ACE2 interface. The receptor binding domain (RBD) is shown in cyan, and the ACE2 is shown in yellow. Pink spheres indicate relative positions of mouse adapting mutations on the RBD, while the blue spheres represent interface residues that differ between human and mouse ACE2 sequences, shown in green and orange, respectively.

Figure 2

Sequence alignment of human and mouse ACE2 highlighting contact points with the SARS-CoV-2 spike receptor binding domain in yellow. Differences between contact points are highlighted in green (human) and orange (mouse), and common contact residues are highlighted in cyan.

Figure 3

Significant occurrences on GISAID of (a) N501Y, E484K, and K417N (nucleotide change G22813T) triple mutations and (b) N501Y, E484K, and K417T triple mutations at the virus receptor binding domain (RBD) since the start of the COVID-19 pandemic (December 31, 2019). These countries are encouraged to perform targeted field surveillance.