Comparative characterization of SARS‐CoV‐2 variants of concern and mouse‐adapted strains in mice

Abstract

SARS‐CoV‐2 has evolved into a panel of variants of concern (VOCs) and constituted a sustained threat to global health. The wildtype (WT) SARS‐CoV‐2 isolates fail to infect mice, while the Beta variant, one of the VOCs, has acquired the capability to infect standard laboratory mice, raising a spreading risk of SARS‐CoV‐2 from humans to mice. However, the infectivity and pathogenicity of other VOCs in mice remain not fully understood. In this study, we systematically investigated the infectivity and pathogenicity of three VOCs, Alpha, Beta, and Delta, in mice in comparison with two well‐understood SARS‐CoV‐2 mouse‐adapted strains, MASCp6 and MASCp36, sharing key mutations in the receptor‐binding domain (RBD) with Alpha or Beta, respectively. Our results showed that the Beta variant had the strongest infectivity and pathogenicity among the three VOCs, while the Delta variant only caused limited replication and mild pathogenic changes in the mouse lung, which is much weaker than what the Alpha variant did. Meanwhile, Alpha showed comparable infectivity in lungs in comparison with MASCp6, and Beta only showed slightly lower infectivity in lungs when compared with MASCp36. These results indicated that all three VOCs have acquired the capability to infect mice, highlighting the ongoing spillover risk of SARS‐CoV‐2 from humans to mice during the continued evolution of SARS‐CoV‐2, and that the key amino acid mutations in the RBD of mouse‐adapted strains may be referenced as an early‐warning indicator for predicting the spillover risk of newly emerging SARS‐CoV‐2 variants.

A SCID Mouse Model To Evaluate the Efficacy of Antivirals against SARS-CoV-2 Infection

“…All mice ( n = 9 per strain) were infected with 10 5 50% tissue culture infective doses (TCID 50 ) of the Beta variant. Based on previous studies where the Beta variant was used to infect wild-type mice ( 14 – 16 ), we selected day 3 postinfection (p.i.) as the endpoint at which all animals were euthanized and lungs were collected to quantify the infectious virus titers.…”

“…In a pseudotype-based entry assay, the pseudoviruses carrying the Beta variant of the spike protein attached more efficiently to the mouse ACE2 receptor than the alpha variants, suggesting that the K417N and E484K mutations in the RBD of the Beta variant may further enhance the binding to the mouse receptor ( 11 ). Recently, a comparative infection study in BALB/c mice revealed that the Beta variant replicates more efficiently than the alpha or delta variant ( 15 ).…”

“…Besides the N501Y mutation, the spike of the Beta B.1.135 variant carries the K417N mutation, which was previously reported in a virulent mouse-adapted SARS-CoV-2 variant ( 13 ). Several studies have shown the ability of the Beta variant to replicate to some extent in WT mouse strains such as C57BL/6 ( 11 , 12 ) and BALB/c ( 14 , 15 ). Here, we wanted to explore whether the Beta SARS-CoV-2 variant replicates more efficiently in severe combined immune deficient (SCID) mice than in wild-type mice and whether, in such a case, SCID mice can be used to develop a sufficiently robust infection model to study the efficacy of small-molecule inhibitors of SARS-CoV-2 infection.…”

A SCID mouse model to evaluate the efficacy of antivirals against SARS-CoV-2 infection

“…In a pseudotype-based entry assay, the pseudoviruses carrying the beta variant spike attached more efficiently to the mouse ACE2 receptor than the alpha variants, suggesting that the K417N and E484K mutations in the RBD of beta variant may further enhance the binding to the mouse recptor (11). Recently, a comparative infection study in BALB/c mice revealed that the beta variant replicates more efficiently than the alpha and delta variant (15).…”

“…Besides the N501Y mutation, the spike of the beta B.1.135 variant carries the K417N mutation that was previously reported in a virulent mouse-adapted SARS-CoV-2 variant (13). Several studies have shown the ability of the beta variant to replicate to some extent in WT mice species such as C57BL/6 (11, 12) and BALB/c (14, 15). Here, we wanted to explore whether the beta SARS-CoV-2 variant replicates more efficiently in severe combined immune deficient (SCID) mice than in the reported wild type mice and whether in such case, SCID mice can be used to develop a suficienlty robust infection model to study the efficacy of small molecules inhibitors of SARS-CoV-2 infection.…”