A University of Ottawa-led team has found a new viral entry for SARS-CoV-2, suggesting it may be able to use proteins to infect a wider range of cells.
Previous studies have shown that SARS-CoV-2 as well as an earlier coronavirus, SARS-CoV-1, the virus behind the SARS outbreak in 2003, enter cells via two distinct pathways. The new research carried out by Dr Marceline Côté’s Faculty of Medicine lab and collaborators shows a third entry route.
This viral entryway involves metalloproteinases, enzymes in the body with a catalytic mechanism that requires a metal, such as zinc atoms, to function.
Over a series of experiments starting in 2020, Dr Côté’s research team discovered that SARS-COV-2 can enter cells in a metalloproteinase-dependent manner. The team describes a role for two matrix metalloproteinases—MMP-2 and MMP-9—in the activation of the spike glycoprotein.
The study published in a recent issue of iScience, suggests that variants that gravitate toward metalloproteinases may cause more havoc.
The team’s experiments showed that some variants clearly prefer the metalloproteinases for activation. For instance, the Delta variant, a more pathogenic variant that surged in 2021, commonly used metalloproteinases for entry. Its less pathogenic successor, Omicron, did not.
“SARS-CoV-2 may be able to use proteins, which are typically secreted by some activated immune cells, to cause more damage and potentially infect a wider range of cells and tissues,” says Dr Côté, a Faculty associate professor who is the holder of the Canada Research Chair in Molecular Virology and Antiviral Therapeutics.
The entry mechanism could also play a role in disease progression.
Dr Côté says the findings could have implications in the progression to severe illness and some post COVID-19 conditions, such as the complex array of post-infection symptoms known as “long Covid.”
The study’s co-first authors are Mehdi Benlarbi, an undergraduate honours’ thesis student in Dr. Cote’s lab and recipient of a uOttawa Centre for Infection, Immunity and Inflammation scholarship, and Dr. Geneviève Laroche of uOttawa. Collaborators include researchers at the University of Western Ontario, Centre de recherche du CHUM, and Sunnybrook Research Institute. Funding was provided by the Canadian Institutes of Health Research (CIHR).
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