A new study from the Dang Lab at the Ragon Institute of Mass General Brigham, MIT, and Harvard, published in the Journal of Experimental Medicine, has found that the body’s immune system inadvertently protects a dangerous fungus from being destroyed, helping to explain why certain infections linger in the lungs for years and can reactivate with life-threatening consequences.

The fungus in question, Cryptococcus neoformans, is one of the most common causes of fungal meningitis worldwide. Most healthy people who breathe in the fungus never get sick. Their immune systems contain it in the lungs inside small structures called granulomas, clusters of immune cells that wall off the infection. But the fungus is not eliminated. It remains dormant, and in people whose immune systems later become weakened, whether by HIV, organ transplantation, or cancer treatment, it can reactivate and spread to the brain, where it is often fatal. Cryptococcal meningitis accounts for roughly one in five AIDS-related deaths globally.

Researchers have long known that a signaling molecule called interferon gamma is critical for fighting Cryptococcus. But even in healthy people with functioning immune systems, the body never fully clears the infection and raises questions as to why this happens.

Using advanced imaging and gene-mapping technology, the team studied the granulomas that form during dormant infection. They found that a specific branch of the immune response, called the type 2 response, was actively working against the body’s ability to kill the fungus. Immune cells called Th2 cells were sending chemical signals that reprogrammed nearby defensive cells. These reprogrammed cells formed a visible ring around the core of the granuloma, essentially creating a barrier that shielded the pathogen.

When the researchers removed the signals driving this reprogramming, or eliminated the Th2 cells entirely, the hosts were able to clear the infection.

The study also overturned a long-held assumption in the field. Scientists had believed that Cryptococcus survives primarily by hiding inside immune cells, where it is shielded from attack. Instead, the team found that the vast majority of the fungus during dormant infection sits outside of cells, in the open space within the granuloma.

The findings suggest a potential new treatment approach. Drugs that block the type 2 immune signals responsible for reprogramming, some of which already exist for other conditions, could theoretically be used to help patients clear latent fungal infections before undergoing immunosuppressive treatments like chemotherapy or transplant surgery, when the risk of reactivation is highest.

The study was co-led by Yufan Zheng and Makheni Jean Pierre. Collaborators included researchers from NIH, Georgetown University, the University of Pennsylvania, Virginia Tech, and the National Cancer Institute.