Mutations that adapt SARS-CoV-2 to mustelid hosts do not increase fitness in the human airway

Zhou, Jie; Peacock, Thomas P.; Brown, Jonathan C.; Goldhill, Daniel H.; Elrefaey, Ahmed M.E.; Penrice-Randal, Rebekah; Cowton, Vanessa M.; Lorenzo, Giuditta De; Furnon, Wilhelm; Harvey, William T.; Kugathasan, Ruthiran; Frise, Rebecca; Baillon, Laury; Lassaunière, Ria; Thakur, Nazia; Gallo, Giulia; Goldswain, Hannah; Donovan-Banfield, I’ah; Dong, Xiaofeng; Randle, Nadine; Sweeney, Fiachra; Glynn, Martha C.; Quantrill, Jessica L.; McKay, Paul F.; Patel, Arvind H.; Palmarini, Massimo; Hiscox, Julian A.; Bailey, Dalan; Barclay, William

doi:10.1101/2021.08.20.456972

Cited by 5 publications

(4 citation statements)

References 54 publications

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“…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.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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

Self Cite

306

344

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show abstract

“…S:F486I has been observed to decrease the affinity of some neutralising antibodies to spike protein (Xu et al, 2021), and may decrease the affinity of spike to ACE2 (Clark et al, 2021), S:F486I has furthermore been associated with mink adaptation (Zhou et al, 2021). S:490L has been observed to reduce the affinity of multiple mAbs as well as decreasing the neutralisation sensitivity of pseudovirus to convalescent sera, however it does not appear to have an impact on viral infectivity (Li et al, 2020).…”

Section: S-gene -Receptor Binding Domain Recurrent Mutationsmentioning

confidence: 99%

Recurrent SARS-CoV-2 Mutations in Immunodeficient Patients

Wilkinson

Richter

Casey

et al. 2022

Preprint

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Long-term SARS-CoV-2 infections in immunodeficient patients are an important source of variation for the virus but are understudied. Many case studies have been published which describe one or a small number of long-term infected individuals but no study has combined these sequences into a cohesive dataset. This work aims to rectify this and study the genomics of this patient group through a combination of literature searches as well as identifying new case series directly from the COG-UK dataset. The spike gene receptor binding domain (RBD) and N-terminal domains (NTD) were identified as mutation hotspots. Numerous mutations associated with variants of concern were observed to emerge recurrently. Additionally a mutation in the envelope gene, - T30I was determined to be the most recurrent frequently occurring mutation arising in persistent infections. A high proportion of recurrent mutations in immunodeficient individuals are associated with ACE2 affinity, immune escape, or viral packaging optimisation. There is an apparent selective pressure for mutations which aid intra-host transmission or persistence which are often different to mutations which aid inter-host transmission, although the fact that multiple recurrent de novo mutations are considered defining for variants of concern strongly indicates that this potential source of novel variants should not be discounted.

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“…Mink and ferret ACE2 are almost identical, potentially explaining the susceptibility of mink to SARS-CoV-2 infection. Although the Y453F containing ferret-adapted SARS-CoV-2 strain showed enhanced binding affinity to both human and ferret ACE2 (Zhou et al, 2021b), this strain is more easily neutralized than the earlier SARS-CoV-2 strains. Hence, the Y453F mutation negatively impacts SARS-CoV-2 replication kinetics in humans, suggesting this mutation is a species-specific adaptive mutation.…”

Section: Ferret Modelmentioning

confidence: 86%

Transmissibility and pathogenicity of SARS-CoV-2 variants in animal models

2022

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SARS-CoV-2 is still one of the most serious public health threats due to its high mortality rate and rapid spread of novel variants. Since the first outbreak in 2019, general understanding of SARS-CoV-2 has been improved through basic and clinical studies; however, knowledge gaps still exist in our understanding of the emerging novel SARS-CoV-2 variants, which impacts the corresponding development of vaccines and therapeutics. Especially, accumulation of mutations in SARS-CoV-2 and rapid spread in populations with previous immunity has resulted in selection of variants that evade the host immune response. This phenomenon threatens to render current SARS-CoV-2 vaccines ineffective for controlling the pandemic. Proper animal models are essential for detailed investigations into the viral etiology, transmission and pathogenesis mechanisms, as well as evaluation of the efficacy of vaccine candidates against recent SARS-CoV-2 variants. Further, the choice of animal model for each research topic is important for researchers to gain better knowledge of recent SARS-CoV-2 variants. Here, we review the advantages and limitations of each animal model, including mice, hamsters, ferrets, and non-human primates, to elucidate variant SARS-CoV-2 etiology and transmission and to evaluate therapeutic and vaccine efficacy.

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Mutations that adapt SARS-CoV-2 to mustelid hosts do not increase fitness in the human airway

Cited by 5 publications

References 54 publications

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

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

Recurrent SARS-CoV-2 Mutations in Immunodeficient Patients

Transmissibility and pathogenicity of SARS-CoV-2 variants in animal models

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