Why Are Some Lungs Protected Against COVID-19?

Investigators identify 11 crucial “protection-defining genes” that prevent a severe disease response to COVID-19 infection.

One of the greatest mysteries surrounding COVID-19 is illness severity. Why do some people experience debilitating “long COVID” or even fatal infection while others are asymptomatic?

Advanced age is one of the greatest risk factors for severe COVID-19 infection. However, new research, published in Cell Reports, suggests the right balance of macrophage immune cells protect people from the worst of COVID-19 disease.

Macrophages are white blood cells, located throughout the body’s tissues to protect the immune system. Macrophages are typically helpful, repairing wounds and consuming harmful, alien pathogens. However, severe COVID-19 infection is now believed to be linked to a hyper-immune response, as macrophages attack the virus as well as the body.

“It’s not the virus itself that makes you critically ill, it’s an overreaction of the immune system,” explained Florian Douam, PhD, a co-leader of the study and an assistant professor of microbiology at the Boston University School of Medicine.

A team of investigators, from the BU National Emerging Infectious Disease Laboratories (NEIDL) and Princeton University, studied lungs that seemed unaffected by COVID-19 infection.

While scientists can access and study the lungs of a person who died of COVID-19, the challenge is examining the lungs of a person with mild or asymptomatic COVID-19 infection. Thus, the investigators engrafted mice with human lung tissue and a human immune system derived from stem cells.

The mice with human lung tissue but no human immune system reacted poorly to COVID-19 infection. However, in the mice with human lungs and immune system, “We were barely seeing any virus in the lungs,” Douam said. “The lung was protected. Then we asked the question, ‘Why is the lung protected?’ And this is where we found the macrophages.”

The investigators found lungs that were more susceptible to COVID-19 disease lacked macrophage diversity. Instead, they predominantly contained the pro-inflammatory macrophage, M1. M1 appeared to drive the hyper-inflammatory response that led to severe COVID-19 disease.

In comparison, the immune systems that had more M2 regulatory macrophages, which aid in wound repair, did not have this extreme autoimmune response. “If you have a more diverse macrophage population that has both regulatory and inflammatory macrophages, you can more effectively regulate the signals driving antiviral responses, shutting them off when appropriate,” said Devin Kenney, a PhD student at BU. “Then, the immune system can clear the virus really rapidly, protect the tissue.”

The investigators noted this positive antiviral response was linked to a set of 11 genes, which they called “protection-defining genes.” In the instances of effective COVID-19 resistance, these 11 genes, associated mainly with the type 1 interferon signaling pathway, had upregulated activity. The study authors emphasized the importance of knowing the specific set of genes macrophages must express to protect the lungs.

The investigators suggested future study into why some immune systems could mobilize a diverse macrophage profile while others could not. A possible solution could be targeted drugs that help balance the immune symptoms. “If you can generate knowledge and better understand the molecular processes driving lung protection from COVID-19,” Douam explained, “you can start designing potential immunotherapy strategies.”