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Emergent SARS-CoV-2 variants: comparative replication dynamics and high sensitivity to thapsigargin

Al-Beltagi, Sarah; Goulding, Leah V.; Chang, Daniel K.E.; Mellits, Kenneth H.; Hayes, Christopher J.; Gershkovich, Pavel; Coleman, Christopher M.; Chang, Kin-Chow

Emergent SARS-CoV-2 variants: comparative replication dynamics and high sensitivity to thapsigargin Thumbnail


Authors

Sarah Al-Beltagi

Leah V. Goulding

Daniel K.E. Chang

KEN MELLITS KEN.MELLITS@NOTTINGHAM.AC.UK
Associate Professor

CHRIS HAYES chris.hayes@nottingham.ac.uk
Professor of Organic Chemistry

CHRISTOPHER COLEMAN CHRISTOPHER.COLEMAN@NOTTINGHAM.AC.UK
Assistant Professor of Infection Immunology

KIN-CHOW CHANG KIN-CHOW.CHANG@NOTTINGHAM.AC.UK
Professor of Veterinary Molecular Medicine



Abstract

The struggle to control the COVID-19 pandemic is made challenging by the emergence of virulent SARS-CoV-2 variants. To gain insight into their replication dynamics, emergent Alpha (A), Beta (B) and Delta (D) SARS-CoV-2 variants were assessed for their infection performance in single variant- and co-infections. The effectiveness of thapsigargin (TG), a recently discovered broad-spectrum antiviral, against these variants was also examined. Of the 3 viruses, the D variant exhibited the highest replication rate and was most able to spread to in-contact cells; its replication rate at 24h post-infection (hpi) based on progeny viral RNA production was over 4 times that of variant A and 9 times more than the B variant. In co-infections, the D variant boosted the replication of its co-infected partners at the expense of its own initial performance. Furthermore, co-infection with AD or AB combination conferred replication synergy where total progeny (RNA) output was greater than the sum of corresponding single-variant infections. All variants were highly sensitive to TG inhibition. A single pre-infection priming dose of TG effectively blocked all single-variant infections and every combination (AB, AD, BD variants) of co-infection at greater than 95% (relative to controls) at 72hpi. Likewise, TG was effective in inhibiting each variant in active preexisting infection. In conclusion, against the current backdrop of the dominant D variant that could be further complicated by co-infection synergy with new variants, the growing list of viruses susceptible to TG, a promising host-centric antiviral, now includes a spectrum of contemporary SARS-CoV-2 viruses.

Citation

Al-Beltagi, S., Goulding, L. V., Chang, D. K., Mellits, K. H., Hayes, C. J., Gershkovich, P., …Chang, K. (2021). Emergent SARS-CoV-2 variants: comparative replication dynamics and high sensitivity to thapsigargin. Virulence, 12(1), 2946-2956. https://doi.org/10.1080/21505594.2021.2006960

Journal Article Type Article
Acceptance Date Nov 11, 2021
Online Publication Date Dec 12, 2021
Publication Date Dec 31, 2021
Deposit Date Nov 18, 2021
Publicly Available Date Mar 28, 2024
Journal Virulence
Print ISSN 2150-5594
Electronic ISSN 2150-5608
Publisher Informa UK Limited
Peer Reviewed Peer Reviewed
Volume 12
Issue 1
Pages 2946-2956
DOI https://doi.org/10.1080/21505594.2021.2006960
Keywords Infectious Diseases; Microbiology (medical); Immunology; Microbiology; Parasitology
Public URL https://nottingham-repository.worktribe.com/output/6729999
Publisher URL https://www.tandfonline.com/doi/full/10.1080/21505594.2021.2006960