Bacterium, virus, coronavirus, COVID-19, sars background
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Researchers at Stanford Medicine say that immune cells in the lungs known as interstitial macrophages are critical in the development of severe—and potentially deadly—COVID. Their findings, published this week in the Journal of Experimental Medicine, showed that the these cells which are located deep in the lungs and normally protective, morph into virus producers when infected with SARS-CoV-2. Once infected the cells release inflammatory and scar-producing chemical signals that can lead to the development of pneumonia and damage the lung tissue to the point where the virus and the secreted substances can break out of the lungs and spread throughout the body.

The research suggests new approaches to help prevent COVID from becoming a life-threatening condition. It also showed why monoclonal antibodies aren’t very effective and only typically work when given very early in the course of the infection, when the virus was still in the upper airways but hadn’t yet infected lung tissue.

“The critical step, we think, is when the virus infects interstitial macrophages, triggering a massive inflammatory reaction that can flood the lungs and spread infection and inflammation to other organs,” said co-senior author Mark Krasnow, MD, PhD, professor of biochemistry and the executive director of the Vera Moulton Wall Center for pulmonary vascular disease.

While blocking this step could be an effective method to treat COVID and represent a significant advance, the researchers noted it is unknown how to block the route the virus takes to get into the cells and better understanding of this alternative mechanism is needed.

The work builds on earlier research by Krasnow and colleagues, published in Nature in 2020 that characterized lung cells, which ultimately led to the creation of an atlas of the more than 50 distinct healthy cells the team identified.

“We’d just compiled this atlas when the COVID-19 pandemic hit,” Krasnow said. Soon afterward, he learned that Catherine Blish, MD, PhD, a professor of infectious diseases and of microbiology and immunology, and Arjun Rustagi, MD, PhD, instructor of infectious diseases and another lead co-author of the study, were building an ultra-safe facility where they could safely grow SARS-CoV-2 and infect cells with it.

Krasnow and Blish soon began collaborating, obtaining fresh healthy lung tissue for seven surgical patients, as well as five deceased lung donors with virus-free lungs. The team then infected the lung tissue with the SARS-CoV-2 virus, waited between one to three days for the virus spread, and then separated and typed the cells to create an infected-lung-cell atlas. This revealed many of the same cells already characterized in Krasnow’s healthy lung cell atlas.

This allowed the researchers to find the differences between health lung cells and infected lung cells, along with how easily the SARS-CoV-2 virus infected these cells and which genes were up regulated and down regulated in the infected cells versus health cells.

Their findings were to counter which cell types were most vulnerable to infection. The assumption has been the cells most susceptible to the virus are alveolar type 2 cells, since their cell surfaces have many copies of ACE2 molecules, which previous research has shown to be a pathway for SARS-CoV-2 to enter cells. This new research showed that alveolar type 2 cells are somewhat vulnerable to the virus, but that two macrophages were, by a large margin, the most frequently infected cells.

Of the two, interstitial macrophages, when infected, pose the greatest risk to a patient. Normally, a last line of immunity defense that protect the alveoli—the one-cell thick airsacks in the lungs where the oxygen that is breathed in enters the bloodstream—interstitial macrophages become infected with SARS-CoV-2 instead of attacking it. Once the virus invades these cells it takes over the production of proteins and nucleic acids inside and as it replicates itself in vast numbers it destroys the boundary between the cell nucleus and the rest of the cell, spilling new copies of the virus out of the cell to infect other cells.

As if this weren’t bad enough, these cells also secrete substances that signal other immune cells throughout the body to move to the lungs. In patients, this results in an influx of inflammatory cells to the lungs and these cells along with fluid that comes with them, prevent the exchange of oxygen from the alveoli to the blood. The damage to the alveoli also allow the virus to move into the blood stream to infect cells in other parts of the body.

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

The team also found that the virus wasn’t gaining access to the interstitial macrophages via ACE2 on the cell surface, rather it entered via a different receptor—CD209.

This finding could explain why monoclonal antibody treatments develop to fight COVID are not effective in treating more advanced disease. Research now can focus on finding a new class of drugs to treat COVID that interfere with the virus’s binding to CD209.

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