Stanford Medicine Study Flags Unexpected Cells in Lung as Suspected Source of Severe COVID

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The airways leading to our lungs culminate in myriad alveoli, minuscule one-cell-thick air sacs, whichare abutted by abundant capillaries. This interface, called the interstitium, is where oxygen in the air we breathe enters the bloodstream and is then distributed to the rest of the body by the circulatory system.

The two kinds of SARS-CoV-2-susceptible lung-associated macrophages are positioned in two different places. So-called alveolar macrophages hang out in the air spaces within the alveoli. Once infected, these cells smolder, producing and dribbling out some viral progeny at a casual pace but more or less keeping a stiff upper lip and maintaining their normal function. This behavior may allow them to feed SARS-CoV-2’s progression by incubating and generating a steady supply of new viral particles that escape by stealth and penetrate the layer of cells enclosing the alveoli.

Interstitial macrophages, the other cell type revealed to be easily and profoundly infected by SARS-CoV-2, patrol the far side of the alveoli, where the rubber of oxygen meets the road of red blood cells. If an invading viral particle or other microbe manages to evade alveolar macrophages’ vigilance, infect and punch through the layer of cells enclosing the alveoli, jeopardizing not only the lungs but the rest of the body, interstitial macrophages are ready to jump in and protect the neighborhood.

At least, usually. But when an interstitial macrophage meets SARS-CoV-2, it’s a different story. Rather than get eaten by the omnivorous immune cell, the virus infects it.

And an infected interstitial macrophage doesn’t just smolder; it catches on fire. All hell breaks loose as the virus literally seizes the controls and takes over, hijacking a cell’s protein- and nucleic-acid-making machinery. In the course of producing massive numbers of copies of itself, SARS-CoV-2 destroys the boundaries separating the cell nucleus from the rest of the cell like a spatula shattering and scattering the yolk of a raw egg. The viral progeny exit the spent macrophage and move on to infect other cells.

But that’s not all. In contrast to alveolar macrophages, infected interstitial macrophages pump out substances that signal other immune cells elsewhere in the body to head for the lungs. In a patient, Krasnow suggested, this would trigger an inflammatory influx of such cells. As the lungs fill with cells and fluid that comes with them, oxygen exchange becomes impossible. The barrier maintaining alveolar integrity grows progressively damaged. Leakage of infected fluids from damaged alveoli propels viral progeny into the bloodstream, blasting the infection and inflammation to distant organs.

Yet other substances released by SARS-CoV-2-infected interstitial macrophages stimulate the production of fibrous material in connective tissue, resulting in scarring of the lungs. In a living patient, the replacement of oxygen-permeable cells with scar tissue would further render the lungs incapable of executing oxygen exchange.

“We can’t say that a lung cell sitting in a dish is going to get COVID,” Blish said. “But we suspect this may be the point where, in an actual patient, the infection transitions from manageable to severe.”

Another point of entry

Compounding this unexpected finding is the discovery that SARS-CoV-2 uses a different route to infect interstitial macrophages than the one it uses to infect the other types.

Unlike alveolar type 2 cells and alveolar macrophages, to which the virus gains access by clinging to ACE2 on their surfaces, SARS-CoV-2 breaks into interstitial macrophages using a different receptor these cells display. In the study, blocking SARS-CoV-2’s binding to ACE2 protected the former cells but failed to dent the latter cells’ susceptibility to SARS-CoV-2 infection.

“SARS-CoV-2 was not using ACE2 to get into interstitial macrophages,” Krasnow said. “It enters via another receptor called CD209.”

That would seem to explain why monoclonal antibodies developed specifically to block SARS-CoV-2/ACE2 interaction failed to mitigate or prevent severe COVID-19 cases.

It’s time to find a whole new set of drugs that can impede SARS-CoV-2/CD209 binding. Now, Krasnow said.

The study was funded by the National Institutes of Health (grants K08AI163369, T32AI007502 and T32DK007217), the Bill & Melinda Gates Foundation, Chan Zuckerberg Biohub, the Burroughs Wellcome Fund, Stanford Chem-H, the Stanford Innovative Medicine Accelerator, and the Howard Hughes Medical Institute.

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