A new study published in the journal Cell pinpoints the likely cell types SARS-CoV-2, a new coronavirus behind the COVID-19 disease, infects; it also shows that one of the human body’s main defenses against viral infections may actually help SARS-CoV-2 infect those very cells.
“We started to look at cells from tissues such as the lining of the nasal cavity, the lungs, and gut, based on reported symptoms and where the SARS-CoV-2 virus has been detected,” said study lead author Dr. Jose Ordovas-Montanes, of Boston Children’s Hospital.
“We wanted to provide the best information possible across our entire spectrum of research models.”
Like the closely related SARS-CoV-1 virus that caused the SARS pandemic, SARS-CoV-2 uses a receptor called ACE2 to gain entry into human cells, aided by an enzyme called TMPRSS2.
That led Dr. Ordovas-Montanes and colleagues to ask a simple question: which cells in respiratory and intestinal tissue express both ACE2 and TMPRSS2?
To address this question, the researchers turned to single-cell RNA sequencing, which identifies which of roughly 20,000 genes are ‘on’ in individual cells.
They found that only a tiny percentage of human respiratory and intestinal cells, often well below 10%, make both ACE2 and TMPRSS2.
Those cells fall in three types: goblet cells in the nose that secrete mucus; lung cells known as type II pneumocytes that help maintain the alveoli (the sacs where oxygen is taken in); and one type of so-called enterocytes that line the small intestine and are involved in nutrient absorption.
Sampling from non-human primates showed a similar pattern of susceptible cells.
“Many existing respiratory cell lines may not contain the full mix of cell types, and may miss the types that are relevant,” Dr. Ordovas-Montanes said.
“Once you understand which cells are infected, you can start to ask, ‘How do these cells work?’ ‘Is there anything within these cells that is critical for the virus’ life cycle?’”
“With more refined cellular models, we can perform better screens to find what existing drugs target that biology, providing a stepping stone to go into mice or non-human primates.”
But it was the study’s second finding that most intrigues the authors.
They discovered that the ACE2 gene is stimulated by interferon — one of the body’s main defenses when it detects a virus.
Interferon actually turned the ACE2 gene on at higher levels, potentially giving the virus new portals to get in.
“ACE2 is also critical in protecting people during various types of lung injury,” Dr. Ordovas-Montanes said.
“When ACE2 comes up, that’s usually a productive response. But since the virus uses ACE2 as a target, we speculate that it might be exploiting that normal protective response.”
Interferons, in fact, are being tested as a treatment for COVID-19. Would they help, or would they do more harm than good? That’s not yet clear.
“It might be that in some patients, because of the timing or the dose, interferon can contain the virus, while in others, interferon promotes more infection,” Dr. Ordovas-Montanes said.
“We want to better understand where the balance lies, and how we can maintain a productive antiviral response without producing more target cells for the virus to infect.”
The findings may also raise new lines of inquiry around ACE inhibitors.
These drugs are commonly used to treat hypertension, which has been linked to more severe COVID-19 disease. Are ACE inhibitors affecting people’s risk?
“ACE and ACE2 work in the same pathway, but they actually have different biochemical properties,” Dr. Ordovas-Montanes said.
“It’s complex biology, but it will be important to understand the impact of ACE inhibitors on people’s physiological response to the virus.”
It’s also too soon to try to relate the study findings to the cytokine storm, a runaway inflammatory response that has been reported in very sick COVID-19 patients.
“It might be that we’re seeing a cytokine storm because of a failure of interferon to restrict the virus to begin with, so the lungs start calling for more help. That’s exactly what we’re trying to understand right now.”
Carly G.K. Ziegler et al. 2020. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell, in press; doi: 10.1016/j.cell.2020.04.035
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