When inhaled, microscopic airborne spores of the fungus Aspergillus fumigatus settle deep in the lungs. In healthy individuals, neutrophils quickly respond by attacking the invading spores and preventing them from growing. However, in people with weakened immune systems, the mold spores can evade immune cells, germinate, and spread to other organs through nearby blood vessels. The resulting infection — known as invasive aspergillosis — can be deadly.

Tobias Hohl, an infectious disease physician and researcher at the Memorial Sloan Kettering Cancer Center, wanted to understand how neutrophils become primed to respond to invading microbes at the precise sites of A. fumigatus  infection with the goal of developing new approaches to preventing or treating such infections. “[Immune] cells like neutrophils are not preprogrammed to kill,” he explained. “They need conditioning; and that conditioning is different for different types of infections.”

In a recent study led by Kathleen Mills, a graduate student in Hohl’s lab, the team showed that A. fumigatus  infection prompts specific lung epithelial cells to produce a cytokine called granulocyte-macrophage colony-stimulating factor (GM-CSF) at local sites of fungal invasion in a mouse model (1). The released GM-CSF helps recruit neutrophils to the infected sites in the lung, enabling these cells to more effectively fight off the invading microbes. The finding opens the possibility of using GM-CSF to prevent or treat invasive aspergillosis in immunocompromised individuals. 

Researchers first discovered GM-CSF in mouse lung tissue, and they initially thought it was a growth factor that could promote the proliferation of bone marrow cells in vitro (2). Later, researchers found that the cytokine played a key role in sustaining alveolar macrophages — specialized immune cells that patrol the lung’s air spaces and defend against inhaled pathogens (3). “Under basal conditions you need GM-CSF in very small amounts in the lung to keep these alveolar macrophages alive,” said Hohl. “In turn, these cells are basically the trash collectors of your lung, and they allow you to keep your airways free and open.” 

The best antifungal drug, the really best, are the neutrophils and our own innate immune cells.
- Tobias Hohl, Memorial Sloan Kettering Cancer Center

However, during A. fumigatus infection, alveolar macrophages alone are insufficient to manage the fungal threat. In response, GM-CSF shifts from its normal role to a more active one, helping to recruit additional immune cells — neutrophils — to join the fight against the invading mold spores (4).

To explore the role of GM-CSF in fighting fungal infection, the research team first infected mice genetically engineered to lack the GM-CSF receptor with A. fumigatus spores. They observed that these mice had a higher proportion of germinating fungal spores compared to mice expressing normal levels of the receptor, indicating that the absence GM-CSF signaling impaired the lung’s ability to fight off the infection. 

Using fluorescence imaging, the researchers then showed that in mice lacking GM-CSF receptors, fewer neutrophils reached the lungs following mold infection, and that those that did had a reduced ability to take up invading A. fumigatus spores. “We could see production of GM-CSF… in exactly the same spots in the lung as where we saw neutrophils coming in and the presence of Aspergillus,” said Mills. “So, it’s not only that these cells — the neutrophils — that are coming into the lung need additional tissue cues once they arrive; it’s that this interaction is hyper-local.”

The team’s findings could pave the way for using GM-CSF to help boost the immune system in patients undergoing chemotherapy or bone marrow transplants, as these individuals are often immunocompromised and at high risk for infection. Currently, antifungal medications are the standard approach to preventing aspergillosis in these patients. “But the best antifungal drug, the really best, are the neutrophils and our own innate immune cells,” Hohl said, noting that recombinant GM-CSF, an FDA-approved drug, could potentially be given as an adjuvant therapy to enhance immune function in vulnerable individuals (5). 

Mills also emphasized that GM-CSF could help improve the effectiveness of currently used antifungal therapies. “There are strains of Aspergillus that are becoming resistant to contemporary antifungal therapy,” she said. “By using some sort of immune targeting therapy like this, that’s maybe an additional way to get around antifungal resistance, which is a growing problem at the moment.”

References

1. Mills K.A.M. et al. GM-CSF–mediated epithelial-immune cell cross-talk orchestrates pulmonary immunity to Aspergillus fumigatus. Sci Immunol  10, eadr0547 (2025).
2. Burgess A.W. et al. Purification and properties of colony-stimulating factor from mouse lung-conditioned medium. J Biol Chem 252, 1998–2003 (1977).
3. Worgall, S. et al. Selective expansion of alveolar macrophages in vivo by adenovirus-mediated transfer of the murine granulocyte-macrophage colony-stimulating factor cDNA. Blood  93, 655–666 (1999).
4. Kasahara, S. et al. Role of granulocyte-macrophage colony-stimulating factor signaling in regulating neutrophil antifungal activity and the oxidative burst during respiratory fungal challenge. J Infect Dis  213, 1289–1298 (2016).
5. Lazarus H.M. et al. Sargramostim (rhu GM-CSF) as Cancer Therapy (Systematic Review) and An Immunomodulator. A Drug Before Its Time? Front Immunol  12, (2021).