Home Immunity Searching for the immune cells that predispose people to severe COVID-19

Searching for the immune cells that predispose people to severe COVID-19


Asst. Professor Huanhuan Joyce Chen of Pritzker Molecular Engineering has conducted a new study showing that the type of macrophages present in a person’s body could determine the likelihood that they will develop severe inflammation in response to COVID-19. 1 credit

When a virus enters a person’s body, one of the first responders to the immune system is a collection of pathogen-eliminating cells called macrophages. But macrophages are diverse; they do not target all viruses equally.

Researchers at the University of Chicago’s Pritzker School of Molecular Engineering (PME) have found that the type of macrophages present in a person’s body may determine the likelihood of them developing severe inflammation in response to COVID-19 . Their study was published in Communication Nature.

“Clinicians know that COVID-19 can cause a spectrum of disease severity from mild to severe symptoms. Why some people, and not others, develop very serious disease is a mystery,” Asst said. Professor Huanhuan Joyce Chen, who led the research with Qizhou Lian from the University of Hong Kong. “This is the first time anyone has linked the variation in symptoms to macrophages.”

A better model for COVID-19 infectionStudying the cellular and molecular effects of the SARS-CoV-2 virus has been a challenge for researchers who typically look to model organisms to mimic human disease; mice, rats and many other animals do not develop the same symptoms of COVID-19 as humans. That’s why, soon after the COVID-19 pandemic began, Chen’s group harnessed human stem cells to study the virus.

As stated previously in NatureChen and his colleagues grew stem cells in functioning mini-lungs and colons — called lung and colon organoids — to probe the effects of SARS-CoV-2 on these organs and screen for drugs to treat the virus.

In the new study, the researchers first analyzed lung biopsies from COVID-19 patients and found that they had particularly high levels of macrophages. To better understand the role of macrophages during COVID-19 infection, Chen’s team developed an approach that could harness the same human stem cell line to become both lung cells and macrophages. The fact that they came from the same initial stem cells was important to prevent immune cells from attacking lung cells.

“This model system provides a perfect way to decode, step by step, how these three components – the immune system, the lungs and the virus – interact,” Chen said.

A cascade of inflammation

When Chen’s lab infected lungs and stem cell-derived macrophages with SARS-CoV-2, they found that not all macrophages responded in the same way. A subset, called M2 macrophages, eliminate the virus by physically engulfing the virus and virus-infected cells in a process known as phagocytosis, while releasing anti-inflammatory molecules.

The M1 macrophages behaved in the opposite way: these cells released a plethora of inflammatory chemical signals that not only fight off SARS-CoV-2, but elicit a more widespread immune response. These same inflammatory factors have been shown to be present in the blood of people with severe symptoms of COVID-19.

“Our results suggest that people who already have activated M1 macrophages in the lungs when infected with COVID-19 may be more likely to develop very severe inflammation from the virus,” Chen said.

Older people and those with certain conditions like hypertension or diabetes — already known to be prone to more severe COVID-19 symptoms — may have higher levels of M1 macrophages, she added.

His team then showed that antibodies, similar to those already used in the clinic to treat COVID-19, helped M2 macrophages eliminate the SARS-CoV-2 virus. More work is needed to show whether the observations hold true in humans, but the results could help inform the prevention or treatment of severe COVID-19 in patients most at risk. And Chen is already thinking about his next experiments with stem cell-derived organoids.

“This model system is useful for decoding the molecular mechanisms behind not only COVID-19, but other infectious diseases,” said Chen.

In the future, his group hopes to make more complex mini-organs that include not only lung and immune cells, but also blood vessels, nerves and other types of supporting cells.

Immune system culprit of severe COVID cases discovered

More information:
Qizhou Lian et al, Differential effects of macrophage subtypes on SARS-CoV-2 infection in a human pluripotent stem cell-derived model, Nature Communication (2022). DOI: 10.1038/s41467-022-29731-5

Provided by the University of Chicago

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