GM-CSF signaling on monocytes and monocyte-derived dendritic cells is required for effective pulmonary immunity to Aspergillus fumigatus.

UNLABELLED: Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), an opportunistic pulmonary infection of immunocompromised patients that can be fatal, despite treatment with modern antifungal drugs. During infection, myeloid cells, such as neutrophils, monocytes, and monocyte-derived dendritic cells (Mo-DCs) are recruited to the lung and are critical for phagocytosing and killing A. fumigatus spores. Recent evidence has shown that intracellular crosstalk between these professional immune cells and other resident pulmonary cell types is required for an effective immune response to A. fumigatus , and that signaling via the cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) is part of this intracellular communication. In this study, we sought to determine a role for GM-CSF signaling on monocytes and their progeny. We harnessed a mouse model of deletion of GM-CSF receptor β chain (encoded by Csf2rb ) in CCR2-expressing cells. Using this model, we found that GM-CSF signaling is required on CCR2 + cells for killing of A. fumigatus and for host survival. This observation expands the importance of GM-CSF in host defense during A. fumigatus pulmonary infection and extends its role in pathways of intracellular crosstalk that mediate effective pulmonary antifungal immunity.

IMPORTANCE: Aspergillus fumigatus was recently designated a critical priority fungal pathogen by the World Health Organization due to its ability to cause fatal pulmonary disease and rapidly increasing acquired antifungal drug resistance. The mechanisms by which cells of the innate immune system cooperate to kill A. fumigatus spores in the lung are incompletely described and warrant further study so that these pathways may be manipulated in patients susceptible to infection. Here, we uncovered a role for the cytokine GM-CSF in coordinating crosstalk between lung epithelial cells and monocytes and monocyte-derived dendritic cells. GM-CSF signaling between these cells is required for fungal killing and host survival, expanding our understanding of the cell types involved in GM-CSF-mediated antifungal immunity.