Human cell types within corresponding organs that express the genes for both ACE2 and CTSL (green dot) or both ACE2 and TMPRSS2 (orange dot).
by Chris Baraniuk
When the SARS-CoV-2 virus enters the human body, it breaks into cells with the help of two proteins that it finds there, ACE2 and TMPRSS2. While there has been much discussion of viral infection in gut and lung cells, researchers have dug into massive gene expression datasets to show that other potential target cells also producing ACE2 and TMPRSS2 are scattered throughout the body—including in the heart, bladder, pancreas, kidney, and nose. There are even some in the eye and brain.
The results, published in a preprint on bioRxiv April 21, show that such cells are strikingly abundant. Many are epithelial cells, which line the outer surface of organs. The new findings add to an emerging picture of SARS-CoV-2 as a virus that can target cells in many places in the human body, rather than being focused on a particular organ or part of the respiratory tract.
Cardiologist Frank Ruschitzka at the University Hospital of Zürich and colleagues separately published a letter in The Lancet April 17 in which they described how virus particles had been found in the vascular endothelium, a thin layer of cells lining blood vessels in various organs of the body, for instance.
“This is not just a virus pneumonia,” Ruschitzka, who was not involved in the latest study, tells The Scientist, referring to COVID-19. “This is a disease like we have never seen before—it is not an influenza, it hits the vessels all over, it hits the heart as well.”
To uncover the locations of cells bearing ACE2 and TMPRSS2, the preprint researchers turned to the Human Cell Atlas, a project that has allowed scientists to pool together data on human cells since 2016.
By scouring single-cell sequencing records of around 1.2 million individual cells from human tissue samples, the team was able to find out which of those cells produce both ACE2 and TMPRSS2, and note their locations in the body. The analysis used 16 unpublished datasets of lung and airway cells and 91 published datasets spanning a range of human organs.
Coauthor Christoph Muus, a graduate student at Harvard University and the Broad Institute, explains that while the data show cells in many locations in the body produce SARS-CoV-2 receptors, it’s not certain that the virus can infect all of those tissues.
“Expressing the receptor is a necessary condition but not necessarily a sufficient condition,” he says. For example, potential target cells were found in the testes, but scientists still don’t know if SARS-CoV-2 infects and replicates in that part of the body.
Jeremy Kamil, a virologist at Louisiana State University Health Shreveport, says the preprint provides important details about the human body that may help scientists understand how SARS-CoV-2 infects hosts. By finding viral protein fragments in tissue samples from patients who died because of COVID-19, scientists might be able to firm up which organs are genuine sites of infection, he adds.
“I’d say this paper gives people a roadmap at where you might want to look in the body to understand where this virus is going,” he says.
One limitation of the work is that relatively little metadata about the people who donated tissue samples were available for the various datasets, though information about age and gender were included in many. The researchers don’t know, for example, whether there was an ethnicity bias in the data, whether patients had pre-existing conditions, or whether they were taking any medications. All of these things could affect gene expression in particular cells.
Smoking status was available for a subset of the data, and the team used this to show that smoking is correlated with a greater expression of the ACE2 gene in the upper airway, but lower expression in certain lung cells. Further research is needed to understand whether this affects smokers’ susceptibility to COVID-19. Data from China suggest that smokers are 14 times more likely to develop a severe form of the disease.
Some researchers from the same group using similar data have also recently published papers in Cell and Nature. In those cases, the researchers focused on certain groups of cells. The study reported in Nature examined cells potentially involved in viral transmission and found that nasal epithelial cells, in particular, were associated with expression of ACE2 and TMPRSS2. The authors report that the virus might exploit cells that secrete fluids in the nasal passage, which might help it spread from one person to another in droplets released, say, when someone sneezes.
The Cell study, meanwhile, also found ACE2 and TMPRSS2 transcripts in nasal, gut, and lung cells but the researchers also found that the protein interferon activated ACE2 expression in vitro. The human body uses interferon to fight infections, so it is not clear whether the protein is of overall benefit or detriment to COVID-19 patients.
The use of so many different data sources backs up the validity of the preprint authors’ findings, says Marta Gaglia, a molecular biologist at Tufts University. She agrees with the researchers that discovering ACE2- and TMPRSS2-producing cells in various places around the body does not prove the virus can always infect such cells.
“I think the reality is that most of the problems come from the lung,” she adds. Plus, while doctors treating COVID-19 patients may detect problems in multiple organs, those issues might not necessarily be caused directly by SARS-CoV-2 infection, says Gaglia. A problematic immune system response, for instance, could damage certain tissues in the body as an indirect consequence of viral infection.
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