Researchers identify the immune cells that keep a deadly fungus in check
A Virginia Tech study finds that control of Cryptococcus neoformans depends not on a single immune cell type, but on several working together — a discovery that could reshape how doctors think about preventing life-threatening fungal infections.
Virginia Tech
image:
(From left) Kirsten Nielsen, Ian Jeong, Priscilla Atim, and Rachel Ber-Murante in the Nielsen Lab. Kirsten Nielsen's research focuses on how the fungal infection cryptococcus shifts from a dormant infection to a harsh and dangerous one.
view moreCredit: Photo by Andrew Mann for Virginia Tech.
Most people carry the fungus Cryptococcus neoformans in their lungs for life and never know it, held in check by the immune system. New research from the Virginia-Maryland College of Veterinary Medicine at Virginia Tech identifies which immune cells do that work — and finds that no single cell type is responsible.
The study, published in the journal mBio, focused on CD4 T cells, the immune system's coordinators. Researchers had long assumed one dominant cell type controlled the infection. Instead, they found several distinct CD4 T-cell populations, each contributing in its own way.
"Everybody assumed we had the queen that was going to be the single most powerful player," said senior author Kirsten Nielsen, professor of microbiology and immunology at the college's Center for One Health Research. "But it turns out it's not just one queen. Imagine playing chess with five queens."
The finding matters because Cyptococcus turns deadly when the immune system falters. In people undergoing chemotherapy, recovering from organ transplants, living with HIV, or taking immune-suppressing drugs, the dormant fungus can reactivate, spread to the brain, and cause meningitis. It kills more than 150,000 people worldwide each year and is the second-leading cause of death among people living with HIV, according to the CDC and World Health Organization.
Doctors currently cannot predict or prevent that reactivation, in part because it was unclear which immune cells were containing the fungus in the first place. Because no single cell type is responsible, the results suggest that any future preventive treatment will need to protect a coordinated network of immune cells rather than target one.
The work is the latest advance in a research program Nielsen has built over more than a decade, tracing to her insight that the outcome of infection is decided in the lungs — not the brain, where symptoms appear. Reproducing the quiet, lifelong lung infection in mouse models took years before her lab, first at the University of Minnesota and now at Virginia Tech, could begin asking which immune cells mattered.
The fungus is also a veterinary concern, infecting cats, dogs, and pet birds. Because animals mount similar immune responses, the findings are expected to inform both human and animal medicine — a connection central to the veterinary college's One Health mission.
"We've added another piece to the puzzle," Nielsen said. "The picture is starting to resolve, but we're still a long way from completing it." Her team has not yet determined how these T cells communicate with the front-line cells they direct — the next step in the work.
The study, "Paradoxical Th1 activation and CTLA-4 regulation is beneficial during latent cryptococcosis," was supported by the National Institutes of Health, with collaborators at Harvard University and the University of Illinois.
Journal
mBio
Article Title
Paradoxical Th1 activation and CTLA-4 regulation is beneficial during latent cryptococcosis
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