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Scientists have discovered which types of cells in the human body may be most susceptible to infection by SARS-CoV-2 virus, identifying putative targets for the pathogen based on the types of proteins produced by the cells.
During the original SARS epidemic in the early 2000s, researchers discovered that the responsible virus, officially designated SARS-CoV, infects cells with the help of two proteins: a receptor called an angiotensin-converting enzyme 2 (ACE2). , which helps the virus bind to cells and an enzyme called serine protease transmembrane type II (TMPRSS2), which mediates cell infection.
Earlier this year, scientists discovered that SARS-CoV-2 – the one that causes COVID-19 – exploits the same two proteins, giving researchers a vital clue to identify the virus’s most susceptible targets at the cellular level: cells in respiratory and intestinal tissue that express both ACE2 and TMPRSS2.
“As soon as we realized that the role of these proteins had been confirmed biochemically, we started looking for where those genes were in our existing data sets,” says immunologist José Ordovas-Montanes of Boston Children’s Hospital.
“We were really in a good position to start investigating which cells this virus could attack.”
In a large multi-agency effort involving dozens of scientists, the researchers analyzed multiple sets of RNA sequencing data, compiling information for thousands of different cell types in humans, non-human primates, and mice.
In particular, the team was looking for gene expression patterns for hundreds of cell types in the lungs, nostrils, and intestine, areas of the body that we know can harbor SARS-CoV-2.
“Because we have this amazing repository of information, we were able to start looking at what would likely be target cells for infection,” says chemical physicist Alex Shalek of MIT.
“Although these data sets were not specifically designed to study [SARS-CoV-2]We hope it gives us a quick start in identifying some of the things that might be relevant there. “
Finally, the analysis revealed that only a small minority of human respiratory and intestinal cells have genes that express both ACE2 and TMPRSS2.
Among those that do, three main cell types were identified: lung cells called type II pneumocytes (which help maintain alveoli, known as alveoli); intestinal cells called enterocytes, which help the body absorb nutrients; and goblet cells in the nasal passage, which secrete mucus.
If both ACE2 and TMPRSS2 need to be in the same cell, or if the soluble forms of TMPRSS2 can float and do the same job, it remains an area for future research. The researchers say knowing the cell types that are the most obvious targets could go a long way in future work, including research into the development of possible antiviral drugs to fight the pandemic.
“This may not be the full story, but it definitely paints a much more accurate picture than where the field was before,” explains Ordovas-Montanes.
“We can now say with some level of confidence that these receptors are expressed in these specific cells in these tissues.”
Among the new results, the team also made a puzzling discovery. A family of immune proteins called interferons, which generally help the body fight infection, stimulates the ACE2 gene that produces the ACE2 protein.
Why this is unknown is still unknown, but it means that one of our body’s natural defense mechanisms against pathogens, in this case, could end up promoting SARS-CoV-2, upregulating the production of the receptor that the virus uses to adhere to cells.
If so, it could be an example of a stealthy evolutionary adaptation, though the researchers say there is much more work to be done to figure out what’s going on here.
“This is not the only example of that,” explains Ordovas-Montanes.
“There are other examples of coronaviruses and other viruses that actually target interferon-stimulated genes as ways to get into cells. In a way, it’s the most reliable host response.”
The findings are reported in Cell.
