SARS-CoV-2 variants of concern Alpha, Beta, Gamma and Delta have extended ACE2 receptor host-ranges

Thakur, Nazia; Gallo, Giulia; Newman, Joseph; Peacock, Thomas P.; Biasetti, Luca; Hall, Catherine N.; Wright, Edward; Barclay, Wendy S.; Bailey, Dalan

doi:10.1101/2021.11.23.469663

Cited by 8 publications

(6 citation statements)

References 32 publications

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“…N501Y mutation, which is present both in B.1.351/Beta and BA.1/Omicron, may play a prominent role in that expanded species tropism. This is in line with previous findings showing in vitro how this mutation may contribute to an increased affinity for murine ACE2 ( Thakur et al, 2021 ).…”

Section: Discussionsupporting

confidence: 93%

Heterogeneous Infectivity and Pathogenesis of SARS-CoV-2 Variants Beta, Delta and Omicron in Transgenic K18-hACE2 and Wildtype Mice

et al. 2022

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The emerging SARS-CoV-2 variants of concern (VOCs) may display enhanced transmissibility, more severity and/or immune evasion; however, the pathogenesis of these new VOCs in experimental SARS-CoV-2 models or the potential infection of other animal species is not completely understood. Here we infected K18-hACE2 transgenic mice with B.1, B.1.351/Beta, B.1.617.2/Delta and BA.1.1/Omicron isolates and demonstrated heterogeneous infectivity and pathogenesis. B.1.351/Beta variant was the most pathogenic, while BA.1.1/Omicron led to lower viral RNA in the absence of major visible clinical signs. In parallel, we infected wildtype (WT) mice and confirmed that, contrary to B.1 and B.1.617.2/Delta, B.1.351/Beta and BA.1.1/Omicron can infect them. Infection in WT mice coursed without major clinical signs and viral RNA was transient and undetectable in the lungs by day 7 post-infection. In silico modeling supported these findings by predicting B.1.351/Beta receptor binding domain (RBD) mutations result in an increased affinity for both human and murine ACE2 receptors, while BA.1/Omicron RBD mutations only show increased affinity for murine ACE2.

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Section: Discussionsupporting

confidence: 93%

Heterogeneous Infectivity and Pathogenesis of SARS-CoV-2 Variants Beta, Delta and Omicron in Transgenic K18-hACE2 and Wildtype Mice

et al. 2022

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“…Pseudovirus bearing Omicron Spike was markedly more able to enter cells using the ACE2 proteins from several species not used efficiently by other SARS-CoV-2 variants, notably domestic poultry, horseshoe bats, and mice (Figure 3C, Supplementary Figure S2). Indeed using the flow cytometry-based binding assay described above we found the full length Omicron Spike protein bound murine ACE2 much more efficiently than even Alpha Spike (Figure 5D), which also contains known mouse adaptation N501Y 19 .…”

Section: Resultsmentioning

confidence: 92%

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

Peacock

Brown

Zhou

et al. 2022

Preprint

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At the end of 2021 a new SARS-CoV-2 variant, Omicron, emerged and quickly spread across the world. It has been demonstrated that Omicrons high number of Spike mutations lead to partial immune evasion from even polyclonal antibody responses, allowing frequent re-infection and vaccine breakthroughs. However, it seems unlikely these antigenic differences alone explain its rapid growth; here we show Omicron replicates rapidly in human primary airway cultures, more so even than the previously dominant variant of concern, Delta. Omicron Spike continues to use human ACE2 as its primary receptor, to which it binds more strongly than other variants. Omicron Spike mediates enhanced entry into cells expressing several different animal ACE2s, including various domestic avian species, horseshoe bats and mice suggesting it has an increased propensity for reverse zoonosis and is more likely than previous variants to establish an animal reservoir of SARS-CoV-2. Unlike other SARS-CoV-2 variants, however, Omicron Spike has a diminished ability to induce syncytia formation. Furthermore, Omicron is capable of efficiently entering cells in a TMPRSS2-independent manner, via the endosomal route. We posit this enables Omicron to infect a greater number of cells in the respiratory epithelium, allowing it to be more infectious at lower exposure doses, and resulting in enhanced intrinsic transmissibility.

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“…The Delta Variant of SARS-CoV-2 has a greater LD100 than Alpha and Beta VOCs in K18-hACE2 mice. To date, most K18-hACE2 mouse or Golden Syrian hamster studies have utilized ancestral viral strains of SARS-CoV-2 (e.g., WA-1, D614G, B.1 Wuhan), and few studies have been performed with emergent VOC (2,17,18,(33)(34)(35)(36)(37)(38)(39). Early studies in K18-hACE-mice with a variety of viral strains used a wide range of challenge doses from as low as 100 PFU to as high as 10 5 PFU (40)(41)(42).…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 Delta variant induces enhanced pathology and inflammatory responses in K18-hACE2 mice

Lee

Wong

Russ

et al. 2022

Preprint

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The COVID-19 pandemic has been fueled by novel variants of concern (VOC) that have increased transmissibility, receptor binding affinity, and other properties that enhance disease. The goal of this study is to characterize unique pathogenesis of the Delta VOC strain in the K18-hACE2-mouse challenge model. Challenge studies suggested that the lethal dose of Delta was higher than Alpha or Beta strains. To characterize the differences in the Delta strain’s pathogenesis, a time-course experiment was performed to evaluate the overall host response to Alpha or Delta variant challenge. qRT-PCR analysis of Alpha- or Delta- challenged mice revealed no significant difference between viral RNA burden in the lung, nasal wash or brain. However, histopathological analysis revealed high lung tissue inflammation and cell infiltration following Delta- but not Alpha-challenge at day 6. Additionally, pro-inflammatory cytokines were highest at day 6 in Delta-challenged mice suggesting enhanced pneumonia. Total RNA-sequencing analysis of lungs comparing infected to uninfected mice revealed that Alpha-challenged mice have more total genes differentially activated, conversely, Delta-challenged mice have a higher magnitude of differential gene expression. Delta-challenged mice have increased interferon-dependent gene expression and IFN-γ production compared to Alpha. Analysis of TCR clonotypes suggested that Delta challenged mice have increased T-cell infiltration compared to Alpha challenged. Our data suggest that Delta has evolved to engage interferon responses in a manner that may enhance pathogenesis. The in vivo and in silico observations of this study underscore the need to conduct experiments with VOC strains to best model COVID-19 when evaluating therapeutics and vaccines.

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SARS-CoV-2 variants of concern Alpha, Beta, Gamma and Delta have extended ACE2 receptor host-ranges

Cited by 8 publications

References 32 publications

Heterogeneous Infectivity and Pathogenesis of SARS-CoV-2 Variants Beta, Delta and Omicron in Transgenic K18-hACE2 and Wildtype Mice

Heterogeneous Infectivity and Pathogenesis of SARS-CoV-2 Variants Beta, Delta and Omicron in Transgenic K18-hACE2 and Wildtype Mice

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

SARS-CoV-2 Delta variant induces enhanced pathology and inflammatory responses in K18-hACE2 mice

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