Researchers in Chicago and Hong Kong have discovered that the type of macrophages present in a person’s body might determine how likely they are to develop severe inflammation in response to COVID-19.
“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 severe disease has been a mystery,” says Huanhuan Joyce Chen, an associate professor at University of Chicago’s Pritzker School of Molecular Engineering. “This is the first time anyone has linked the variation in symptoms to macrophages.”
Macrophages act like an immune system’s first responder when a virus makes its way into a person’s body. But these pathogen-removing cells are diverse; they don’t all target viruses in the same way. Some macrophages help the human body fight SARS-CoV-2 without systemic inflammation.
Using organoids developed in a previous study, Chen and colleagues report in Nature Communications that an aggressive subset of macrophages starts a cascade of events that can lead to multi-organ failure in COVID-19 patients.
The team first analyzed lung biopsies from COVID-19 patients and discovered that they had especially high levels of macrophages. To better understand the role of macrophages during a COVID-19 infection, Chen’s team then developed an approach that could exploit the same line of human stem cells to become both lung cells and macrophages simultaneously. The fact that they arose from the same initial stem cells was important to prevent the immune cells from attacking the 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,” said Chen.
When Chen’s lab infected the stem cell-derived lungs and macrophages with SARS-CoV-2, they found that not all macrophages responded in the same way. One subset, dubbed M2 macrophages, eliminates the virus by physically engulfing virus and virus-infected cells in a process known as phagocytosis, while releasing anti-inflammatory molecules.
M1 macrophages, on the other hand, released a plethora of inflammatory chemical signals that not only fight SARS-CoV-2, but cause a more widespread immune response. These same inflammatory factors have been shown to be present in the blood of people with severe COVID-19 symptoms.
“Our results suggest that people who already have M1 macrophages activated in the lungs when infected with COVID-19 might be more likely to develop very severe inflammation from the virus,” said Chen. Elderly 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 the M1 macrophages, she added.
Her team went on to show that antibodies—similar to those already used clinically to treat COVID-19—helped M2 macrophages clear the SARS-CoV-2 virus. More work is needed to show whether the observations hold true in humans, but the findings could help inform the prevention or treatment of severe COVID-19 in the most at-risk patients.
Chen is already thinking ahead to her next experiments with the 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, the group hopes to make more complex mini-organs that include not only lung and immune cells, but blood vessels, nerves and other supporting cell types.