Immune Cells Are the Most Susceptible to COVID Lung Infections: Stanford Study

Immune cells meant to protect the lungs from viral and bacterial infections are actually the most susceptible to COVID-19 infections, a new Stanford University study found.

For decades, scientists have assumed that infections in the respiring lung cells drive respiratory infections.

“It was a straightforward experiment, and the questions we were asking were obvious,” co-senior author Dr. Mark Krasnow said in the study’s press release. “It was the answers we weren’t prepared for.”

When infected, these immune cells become something akin to viral factories, producing high levels of the virus while sending out inflammatory signals to recruit more immune cells to the infection site. This causes a profound inflammatory response in the lungs.

These Immune Cells Help the Virus Replicate

The researchers infected slices of donated lungs with the original COVID-19 Wuhan variant. They then harvested and sequenced the cells to see which cell types had the highest viral levels.

“Cells with high viral levels … were rare and restricted to six cell types,” the authors wrote. One type was the alveolar cells responsible for gas exchange, the primary predicted lung target of COVID-19-causing SARS-CoV-2. Other types included cells that formed tissues and several immune cells.

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“Macrophages were the most prominent lung targets,” the authors found. These were, namely, alveolar and interstitial macrophages.

Macrophages are large immune cells that make up the first lines of defense. They routinely engulf protein and debris around them, surveying the body for foreign invaders.

Alveolar macrophages patrol inside the lungs’ air sacs and interact with external pathogens entering the body.

Interstitial macrophages occupy the thin tissues where air exchange occurs intermittently near the blood vessels. During a viral infection, they become compromised and help the virus replicate, enacting a more potent inflammatory response than that of the alveolar macrophages.

“It’s really a much more dramatic inflammatory response in which the virus replicates a lot. That induces a robust antiviral response, which then can recruit other cells, which is not ideally what you actually want because it can fill the airspace with junk from the inflammation,” co-senior author and Stanford professor of medicine Dr. Catherine Blish told The Epoch Times.

The strong inflammatory response from the interstitial macrophages may be the driver that makes a COVID-19 case severe, the study suggests.

Long-Standing Belief Questioned

The study, published in the Journal of Experimental Medicine on April 10, questions a long-standing assumption that respiratory infections primarily infect respiring lung tissues.

This assumption drove research to focus on lung tissues and cells, disregarding whether other cells may be more susceptible.

Dr. Blish said whether other respiratory viruses, like influenza, target immune cells over respiring lung cells is still unknown.

“Likely no, but we’ll see,” she said. “I think this is something that would have to be studied virus by virus because different viruses have [different] mechanisms.”

Additionally, because researchers found that SARS-CoV-2 can infect human cells in the upper airways using two receptors, ACE2 and CD147, most research on the virus has focused on these receptors.

Severe COVID-19 tends to exhibit signs of inflammation in the lower lungs, which is where the interstitial macrophages are located. The authors also found that the virus does not use ACE2 or CD147 receptors to infect macrophages.

Instead, the virus likely enters through another receptor known as CD209.

Therefore, the authors speculated that treatments that can block the CD209 receptor may help prevent a severe COVID-19 infection.

“It also potentially provides an explanation for why the antibodies that block the two cell-mediated entries (ACE2 and CD147) don’t do any good when they’re given late into the infection,” Dr. Blish said.

Study Suggests Reason Steroids Work for Severe COVID-19

The study findings may explain why steroids work for treating severe COVID-19.

“Immune cell activation is a key component of severe COVID, and it likely explains why immune suppressants like steroids are helpful in severe COVID treatment,” Dr. Arjun Rustgai, a researcher and instructor of medicine at Stanford University, told The Epoch Times.

The RECOVERY study found that prescribing dexamethasone, a type of steroid, to patients with severe COVID-19 reduced mortality from 40 percent to 30 percent.

Steroids are a class of anti-inflammatory drugs that suppress immune and inflammatory activities. They were also highly controversial early on in the COVID-19 pandemic.

At the start of the pandemic, some critical care doctors advocated trying steroids in severe patients as a way of combating inflammation.

Pulmonary critical care physician Dr. Pierre Kory was an early advocate of this treatment. He recognized that the organized pneumonia, or lung inflammation, involved in severe COVID-19 needs steroids to control the inflammation.

However, some doctors and hospital systems hesitated to try it due to the initial lack of clinical trials. Some of the reluctance also revolved around steroids’ suppression of the immune system, which may cause a person to become more susceptible to worse outcomes if they are used early in the disease.