TGen

Nicholas Banovich

Research papers in the journals Cell and Nature Medicine have identified cells that act as major coronavirus infection sites — and the proteins that make them vulnerable.

The findings stem from hundreds of scientists working together and sharing data.

The protein spikes that make up a coronavirus's "crown" infect cells through chemical doorways called receptors.

Using new sequencing methods, researchers found two proteins that prop open the door for SARS-CoV-2, the virus that causes the COVID-19 disease, were prevalent in special nasal bodies called goblet cells and ciliated cells.

Goblet cells maintain the body's protective barriers by secreting mucus and immune agents like anti-microbial proteins. Ciliated cells use tiny hair-like structures to sweep the nose clean of dust, bacteria and other debris.

Co-author Nick Banovich of TGen said the virus might shelter in the upper airway before spreading into the lower respiratory tract.

"So if we could come up with an intranasal antiviral, it might more effectively knock out the virus," he said.

The findings agree with previous studies showing higher viral loads in nasal swabs than in throat swabs in both symptomatic and asymptomatic patients, suggesting surface tissues within the nose — where goblet and ciliated cells reside— as an entry point for initial infection and transmission.

Banovich, who researches why lung diseases affects some people differently than others, contributed to the study as a member of the Lung Biological Network of the Human Cell Atlas, a working group of hundreds of scientists around the world who seek to describe every cell in the human body.

He said advances in sequencing technology were essential to the research.

Older sequencing methods ground up entire tissue samples and analyzed them as a single mass of cells, which limited the specificity of the results.

"If you're talking about a tissue like the lung, there's maybe 30, 40 different types of cells in there. And so what you get when you grind everything up together as just a composite overview of everything that's there," said Banovich.

Conversely, massively parallel single-cell RNA sequencing lets scientists look at individual cells by the thousands, all at once, which produces a very high resolution view of individual cells.

"We could look to see what types of cells were expressing the genes that were necessary for SARS-CoV-2 to enter the cell," said Banovich.

Those cells contained two key proteins: ACE2 (angiotensin-converting enzyme 2), the receptor that lets the coronavirus "dock" with the cell, and TMPRSS2 (transmembrane protease, serine 2), which allows it inside.

Previous research had identified ACE2 as the receptor for SARS, COVID-19's closest relative among the coronaviruses.

"A lot of this knowledge actually came from studies that were done on the original SARS virus, and we're finding most of these principles also apply to SARS-CoV-2 as well," said Banovich.

One concerning finding involved the roles interferons might play in the virus's spread.

Normally, interferon genes make signaling proteins that aid in a cell's immune response. But in SARS-CoV-2, they can bolster ACE2 levels in the affected cell and its neighbors, which means interferons could help or harm, depending on timing.

"You need that interferon response to fight the infection but, if it turns on potentially at the wrong time in this process, instead of attacking the infection, it could just be making this a more target rich environment for the virus," said Banovich.

The authors hope the results will contribute to a better understanding of the virus's infection routes and possible treatment targets.