Ancestral, Delta, and Omicron (BA.1) SARS-CoV-2 strains are dependent on serine proteases for entry throughout the human respiratory tract

Matthew J Gartner; Leo Yi Yang Lee; Francesca L Mordant; Randy Suryadinata; Joseph Chen; Philip Robinson; Jose M Polo; Kanta Subbarao

doi:10.1016/j.medj.2023.08.006

Ancestral, Delta, and Omicron (BA.1) SARS-CoV-2 strains are dependent on serine proteases for entry throughout the human respiratory tract

Med. 2023 Dec 8;4(12):944-955.e7. doi: 10.1016/j.medj.2023.08.006. Epub 2023 Sep 27.

Authors

Matthew J Gartner¹, Leo Yi Yang Lee¹, Francesca L Mordant¹, Randy Suryadinata², Joseph Chen³, Philip Robinson⁴, Jose M Polo⁵, Kanta Subbarao⁶

Affiliations

¹ Department of Microbiology and Immunology, the University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.
² Department of Respiratory Medicine, Royal Children's Hospital, Parkville, VIC 3052, Australia; Infection and Immunity, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
³ Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia.
⁴ Department of Respiratory Medicine, Royal Children's Hospital, Parkville, VIC 3052, Australia; Infection and Immunity, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Paediatrics, the University of Melbourne at the Royal Children's Hospital, Parkville, VIC 3052, Australia.
⁵ Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC 3800, Australia; Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia; Adelaide Centre for Epigenetics, University of Adelaide, Adelaide, SA 5005, Australia; South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA 5005, Australia.
⁶ Department of Microbiology and Immunology, the University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; WHO Collaborating Centre for Reference and Research on Influenza, the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia. Electronic address: [email protected].

PMID: 37769654
DOI: 10.1016/j.medj.2023.08.006

Abstract

Background: The SARS-CoV-2 Omicron BA.1 variant emerged in late 2021 and became the globally dominant variant by January 2022. Authentic virus and pseudovirus systems have shown Omicron spike has an increased dependence on the endosomal pathway for entry.

Methods: We investigated the entry mechanisms of Omicron, Delta, and ancestral viruses in cell models that represent different parts of the human respiratory tract, including nasal epithelial cells (hNECs), large-airway epithelial cells (LAECs), small-airway epithelial cells, and embryonic stem cell-derived type II alveolar cells.

Findings: Omicron had an early replication advantage in LAECs, while Delta grew to higher titers in all cells. Omicron maintained dependence on serine proteases for entry in all culture systems. While serine protease inhibition with camostat was less robust for Omicron in hNECs, endosomal entry was not enhanced.

Conclusions: Our findings demonstrate that entry of Omicron BA.1 SARS-CoV-2 is dependent on serine proteases for entry throughout the respiratory tract.

Funding: This work was supported by The Medical Research Future Fund (MRF9200007; K.S., J.M.P.) and the DHHS Victorian State Government grant (Victorian State Government; DJPR/COVID-19; K.S, J.M.P.). K.S. is supported by a National Health and Medical Research Council of Australia Investigator grant (APP1177174).

Keywords: Omicron variant; Pre-clinical research; SARS-CoV-2 entry; human airway epithelial cells; serine proteases.

MeSH terms

COVID-19* / epidemiology
Humans
Respiratory System
SARS-CoV-2 / genetics
Serine Endopeptidases / genetics
Serine Proteases* / genetics

Substances

Serine Proteases
Serine Endopeptidases