How COVID-19 Coronavirus Beats The Immune System And Gets Into Lung Tissue

We’ve heard a lot about how COVID-19 coronavirus is transmitted and how it effects the body. We were introduced to medical terms like cytokine storm, hydroxychloroquine and viral shedding. But how does the virus do its work? How does it beat our defenses and attack respiratory tissue?

For some people, the SARS-CoV-2 virus is a dire threat to their health and their lives. But why? What makes COVID-19’s attacks on respiratory tissue so effective? Alex K. Shalek, PhD, of MIT and Jose Ordovas-Montanes, PhD, of Boston Children’s Hospital have just published a study which dug into that question. The study was published April 21 in the journal Cell.

They were seeking to pinpoint the most likely types of cells for infection by the virus. They hoped to lay the groundwork for understanding what SARS-CoV-2 does in the body, what makes some people more likely to get infected and get seriously ill and how to find treatments that work. What surprised them was the fact that one of the body’s primary defenses against viral attack may actually be helping the virus infect those very same cells.

The researchers had a bit of a head start. At the time of the Wuhan outbreak, Shalek and Ordovas-Montanes were already researching various respiratory cell types in humans, primates and mice.

“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 virus has been detected,” says Ordovas-Montanes. “We wanted to provide the best information possible across our entire spectrum of research models.”

Which cells are COVID-19-susceptible?

We know from previous research that SARS-CoV and SARS-CoV-2 both use a receptor called ACE2 to get into human cells. This process is sped along by an enzyme called TMPRSS2. That led the two researchers to ask the next logical question: Which cells in respiratory tissue express both TMPRSS2 and ACE2?

They believed the answer to that question could be found by using single-cell RNA sequencing. This process tells researchers which of the approximately 20,000 genes are “switched on” in any individual cell. What they learned was that only a small percentage – often less than 10 percent – of human respiratory cells make both TMPRSS2 and ACE2.

The cells in question are of three types. Goblet cells in the nose are cells that secrete mucus. In the lungs, pneumocytes help maintain the alveoli, the small sacs where oxygen is absorbed. The last type, enterocytes, line the small intestine and function in nutrient absorption. All three types also express both ACE2 and TMPRSS2. They noted a similar pattern of susceptible cells in non-human primates, too.

“Many existing respiratory cell lines may not contain the full mix of cell types, and may miss the types that are relevant,” Ordovas-Montanes notes. “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’s 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.”


This important realization wasn’t the most interesting, according to the scientists. They also found that the ACE2 gene is stimulated by interferon. This gene is the one which encodes the receptor which SARS-CoV-2 exploits to enter human cells. Interferon is one of the body’s main defenses against viruses. But in this case, interferon actually turned on the ACE2 gene, and at higher levels, possibly paving the way for the virus to get in.

“ACE2 is also critical in protecting people during various types of lung injury,” notes Ordovas-Montanes. “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.”

Interestingly, interferons are among the compounds being tested to treat COVID-19. The jury is still out on whether they will help or make things worse.

“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,” says Ordovas-Montanes. “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.”

Cytokine storms and questions about ACE inhibitors

Did this research reveal more about the role ACE inhibitors may play in determining if certain people get COVID-19? They are commonly prescribed to treat high blood pressure, but they could be increasing people’s risk.

“ACE and ACE2 work in the same pathway, but they actually have different biochemical properties,” Ordovas-Montanes cautions. “It’s complex biology, but it will be important to understand the impact of ACE inhibitors on people’s physiological response to the virus.”

As for cytokine storms, the story remains incomplete there as well. Cytokine storms are essentially uncontrolled inflammatory responses which have been reported in severe to critical cases of COVID-19. Cytokines are called on to respond when infection is detected. Interferon is one of those cytokines.

“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.”

Next up for the team is looking into what the virus is doing within the cells it targets. Along with studying tissue samples from children and adults, this will allow the team to better grasp the reasons why COVID-19 seems to be less severe in younger people.

Getting a better understanding of how the virus gets into respiratory tissue may well open up new lines of treatment for COVID-19. After you wade through all the cell talk and virus lingo, that’s the really good news you find at the end.

Keep the faith and keep after it!

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