Mouse Adapted SARS-CoV-2 protects animals from lethal SARS-CoV challenge

Abstract

The emergence of SARS-CoV-2 has resulted in a worldwide pandemic causing significant damage to public health and the economy. Efforts to understand the mechanisms of COVID-19 disease have been hampered by the lack of robust mouse models. To overcome this barrier, we utilized a reverse genetic system to generate a mouse-adapted strain of SARS-CoV-2. Incorporating key mutations found in SARSCoV-2 variants, this model recapitulates critical elements of human infection including viral replication in the lung, immune cell infiltration, and significant in vivo disease. Importantly, mouse-adaptation of SARS-CoV-2 does not impair replication in human airway cells and maintains antigenicity similar to human SARS-CoV-2 strains. Utilizing this model, we demonstrate that SARS-CoV-2 infected mice are protected from lethal challenge with the original SARS-CoV, suggesting immunity from heterologous CoV strains. Together, the results highlight the utility of this mouse model for further study of SARS-CoV-2 infection and disease.

The altered entry pathway and antigenic distance of the SARS-CoV-2 Omicron variant map to separate domains of spike protein

“…Substitutions within the Spike RBD have been shown to alter the host-tropism of SARS-CoV-2, leading to enhanced replication in mice, ferrets, or mink 15-17 . Separately, recent studies from the US have established that white-tailed deer can act as a reservoir for the virus 18 , highlighting a potential future issue for the pandemic.…”

But Mouse, you are not alone: On some severe acute respiratory syndrome coronavirus 2 variants infecting mice

“…The residues 75 to 82 in mACE2 are significantly different from hACE2 (Table 2), therefore any mutation in the corresponding RBD interface is worth investigation. We could find one from experimental observations, the engineered substitution F486L, 27 and consider it to have at best an enhancing role. As it was observed simultaneously with Q498Y (which is likely to sustain mouse infectivity on its own), the contribution of F486L to the overall mouse adaptation remains to be ascertained.…”

“…Further details are provided under Supplementary Methods for Molecular Modelling. We then compared our insilico findings with experimental results reported by different research groups with mouse adapted strains/isolates [6][7][8]13,[21][22][23][24][25][26][27][28][29] and VOC 14,[30][31][32][33][34] (Table 1). Taken together, we were able to gain valuable insights into the likely effects of different mutations of consequence.…”

“…It is unsurprising that the latter variants requiring two or more changes were rarely observed in situ regardless of their high in vitro affinity scores from Starr et al 38 From the above and Table 3, we see that in silico analysis can provide valuable insights to interpret and bridge in vitro, in vivo and in situ observations on the RBD position 501. A similar analysis is possible with the alternative essential mutation for mouse adaptation at RBD position 498, where the in vitro affinity enhancement order is H498, Y498, F498 and W498 according to Starr et al 38 Of these, H498 (on its own) and Y498 (with enhancing RBD mutations) have been shown to result in mouse adaptation in vivo (Table 1); 7,8,[23][24][25][26][27][28] Q498R was also reported once, unusually in combination with N501Y, isolated from mouse lung after 30 passages. However, in situ observations of these variants have been limited to R498 ( 15occurrences) and H498 (3 occurrences) so far.…”

“…The copyright holder for this preprint this version posted August 5, 2021. ; https://doi.org/10.1101/2021.08.04.455042 doi: bioRxiv preprint enhancement order is H498, Y498, F498 and W498 according to Starr et al 38 Of these, H498 (on its own) and Y498 (with enhancing RBD mutations) have been shown to result in mouse adaptation in vivo (Table 1); 7,8,[23][24][25][26][27][28] Q498R was also reported once, unusually in combination with N501Y, isolated from mouse lung after 30 passages. However, in situ observations of these variants have been limited to R498 ( 15occurrences) and H498 (3 occurrences) so far.…”