The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 mice

Abstract

The alpha/B.1.1.7 SARS-CoV-2 lineage emerged in autumn 2020 in the United Kingdom and transmitted rapidly until winter 2021 when it was responsible for most new COVID-19 cases in many European countries. The incidence domination was likely due to a fitness advantage that could be driven by the receptor-binding domain (RBD) residue change (N501Y), which also emerged independently in other variants of concern such as the beta/B.1.351 and gamma/P.1 strains. Here, we present a functional characterization of the alpha/B.1.1.7 variant and show an eightfold affinity increase towards human angiotensin-converting enzyme-2 (ACE-2). In accordance with this, transgenic hACE2 mice showed a faster disease progression and severity after infection with a low dose of B.1.1.7, compared to an early 2020 SARS-CoV-2 isolate. When challenged with sera from convalescent individuals or anti-RBD monoclonal antibodies, the N501Y variant showed a minor, but significant elevated evasion potential of ACE-2/RBD antibody neutralization. The data suggest that the single asparagine to tyrosine substitution remarkable rise in affinity may be responsible for the higher transmission rate and severity of the B.1.1.7 variant.

Differential Pathogenesis of SARS-CoV-2 Variants of Concern in Human ACE2-Expressing Mice

“…Our results corroborated the recent findings that the alpha, beta, and delta variants were able to cause enhanced disease in K18-hACE2 mice [6,14,31,32]. In the present study, we did not conduct a comprehensive transcriptome analysis of mice lungs and brain that were infected with SARS-CoV-2 variants.…”

“…Most recently, the omicron (B.1.1.529) VoC that emerged in South Africa was estimated to have been responsible for the majority of infections worldwide. The B.1.1.7 variant has mutations in the receptor binding domain (RBD) region, including N501Y, 69/70 deletion, and P681H near the S1/S2 furin cleavage site [7,[12][13][14]. The B.1.351 variant has eight mutations, of which the three most notable mutations are K417N, E484K, and N501Y in the spike protein [3,7,9,15].…”

Differential pathogenesis of SARS-CoV-2 variants of concern in human ACE2-expressing mice

“…B.1.1.7 and B.1.351 caused lethal disease in K18-hACE2 mice accompanied with high tittered viral burdens in the lungs and brain. Our results corroborated with the recent findings that alpha and beta variants were able to cause enhanced disease in K18-hACE2 mice [6,7,14,28]. The B.1.617.2 (delta) lineage does not harbor the N501Y substitution in the spike protein but does have additional mutations within the spike protein which diverge from other VoC.…”

“…Most recently, omicron (B.1.1.529) VoC that emerged in South Africa is estimated to have been responsible for majority of infections worldwide. The B.1.1.7 variant has mutations in the receptor binding domain (RBD) region, including N501Y, 69/70 deletion, and P681H near the S1/S2 furin cleavage site [7,[12][13][14]. The B.1.351 variant has eight mutations, of which the three most notable mutations are K417N, E484K, and N501Y in the spike protein [3,7,9,15].…”

Diet induced obesity and type 2 diabetes drives exacerbated sex-associated disease profiles in K18-hACE2-mice challenged with SARS-CoV-2

“…The Alpha variant (strain B.1.1.7) of SARS-CoV-2 emerged in the United Kingdom in the spring of 2021 and moved rapidly across the globe. Alpha seemed to have enhanced virulence compared to ancestral strains of the virus in K18-hACE2-mice as well as other preclinical animal models (55,(62)(63)(64)(65)(66)(67). Due to the significance of Alpha variant's dominance among circulating strains in humans, we used this VOC to study the effects of DIO and Type 2 Diabetes in the K18-hACE2 mouse model of SARS-CoV-2 infection.…”