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In late 2021, Omicron BA.1 appeared and quickly became the most widespread variant of SARS-CoV-2. Although it spreads more easily than the original strain and the Delta variant, it appears to cause less severe infections.

Numerous studies investigated the reasons behind these differences, and a common suggestion was that Omicron has changed how the virus enters cells. However, new research led by the Doherty Institute found results different to previous research that used laboratory-made cells and engineered viruses.

Researchers looked at how the Omicron, Delta, and original strains of the SARS-CoV-2 virus enter different types of cells in the human respiratory tract, including those in the nose, large airways, small airways and lung cells.

The University of Melbourne’s Dr Matthew Gartner, a Research Officer at the Doherty Institute and first author of the study published in Med, explained that there are two ways SARS-CoV-2 can enter the cells to infect them.

“One way the virus can get in is through the cell surface, using a specific kind of protein called ‘serine proteases’ to break through the cell’s protective barriers. Think of this method like delivering mail directly to someone’s front door,” Dr Gartner explained.

The other method is the ‘endosomal’ pathway. Cells are surrounded by a complex environment of lipids, carbohydrates and proteins. To make use of these resources, cells take in external molecules, a process called endocytosis. Think of the endosomal network like a cell’s postal service, sorting through mail for delivery to a specific location. Viruses have evolved the ability to enter cells during this process.

“Previous studies using laboratory-made cells suggested Omicron preferred the ‘postal service’ (endosomal entry) route into cells. In our study, we found that when the Omicron variant of the virus tries to get inside cells that are like the ones in our respiratory tract, it doesn't use the ‘postal service' method (endosomal entry) as much as was thought. Instead, it still relies on the ‘front door’ method (serine proteases) to enter these cells, just like the original virus.”

Additionally, the researchers observed that Omicron initially replicated faster than earlier variants in large airway cells. However, the Delta variant ultimately reached the highest virus levels in all parts of the human respiratory tract they studied. This explains why Omicron infection tends to be less severe, even with resistance to antibodies from vaccinated individuals and some treatments, compared to the Delta variant.

Royal Melbourne Hospital’s Professor Kanta Subbarao, Director of the WHO Collaborating Centre for Reference and Research on Influenza at the Doherty Institute and senior author of the paper, said that these findings highlight the importance of using realistic cell culture systems to study how new variants of the virus function.

“Understanding how each virus variant enters cells at different sites in the respiratory tract is crucial for the development of effective treatment that relies on blocking entry into the cells,” she said.

“We won’t be able to block the virus if we don’t know where it goes. Based on our findings, drugs preventing entry of the virus through the ‘front door’ would continue to be effective in reducing Omicron infection.”

Peer review: Med (DOI: https://doi.org/10.1016/j.medj.2023.08.006) 

Funding: The Medical Research Future Fund, DHHS Victorian State Government grant (Victorian State Government) and the National Health and Medical Research Council of Australia Investigator grant