“Clinicians know that COVID-19 can cause a spectrum of disease severity from mild to severe symptoms. Why some people, but not others, develop very severe disease has been a mystery,” said Assistant Professor Joyce Chen, who Led the research with Qizhou Lian of the University of Hong Kong. “This is the first time that changes in symptoms have been linked to macrophages.”
Studying the cellular and molecular effects of the SARS-CoV-2 virus has been a challenge for researchers, who often turn to model organisms to mimic human disease because mice, rats and many other animals do not develop the same COVID-19 that humans do -19 symptoms. That’s why, shortly after the COVID-19 pandemic began, Joyce Chen’s lab used human stem cells to study the virus.
New findings from Joyce Chen’s lab could inform the process of preventing or treating the most at-risk patients
As previously reported in the journal Nature, Chen and her colleagues grew stem cells into normal mini-lungs and colons, or lung and colon organs, to explore the effects of SARS-CoV-2 on these organs and to screen for therapeutics against the virus. drug.
In the new study, 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 a method that uses the same lineage of human stem cells to become lung cells and macrophages at the same time. The fact that they arise from the same naive stem cells is important in preventing immune cells from attacking lung cells. This model system provides a way to decode step-by-step how these three components — the immune system, the lungs and the virus — interact.
When Chen’s lab infected stem cell-derived lung and macrophages with SARS-CoV-2, they found that not all macrophages responded the same way. A subset of these cells, known as M2 macrophages, eliminate viruses by physically engulfing them and virus-infected cells in a process known as phagocytosis, while releasing anti-inflammatory molecules.
M1 macrophages behave in the opposite way: These cells release a flood of inflammatory chemical signals that not only fight SARS-CoV-2, but elicit a broader immune response. These same inflammatory factors have been shown to be present in the blood of people with severe COVID-19 symptoms.
Assistant Professor Joyce Chen (here in collaboration with graduate student Xu jingwen) has previously investigated the effects of SARS-CoV-2 on lung and colon organs
“Our results suggest that people who already have M1 macrophages activated in their lungs may be more likely to develop very severe inflammation from the virus when infected with COVID-19,” Chen said. The elderly and those with certain diseases such as People with high blood pressure or diabetes — who have been known to be prone to more severe COVID-19 symptoms — may have higher levels of M1 macrophages.”
Her team also found that antibodies — similar to those already clinically used to treat COVID-19 — help M2 macrophages clear the SARS-CoV-2 virus. More work is needed to prove whether these observations hold in humans, but the findings could help prevent or treat severe COVID-19 in the most at-risk patients. The team is already thinking about the next stem cell-derived organ experiment. This model system helps to decode not only the molecular mechanisms behind COVID-19, but other infectious diseases as well.
In the future, her group hopes to create more complex mini-organs that include not only lung and immune cells, but also blood vessels, nerves and other supportive cell types.