Early inflammatory macrophage reprogramming by Scedosporium apiospermum determines fungal survival

Scedosporium is the second most prevalent fungal colonizer of the airways of cystic fibrosis (CF) patients after Aspergillus fumigatus. Chronic bacterial and fungal colonization drives persistent inflammation via damage-associated molecular patterns, contributing to lung injury. Owing to their distinct structural and biological properties, S. apiospermum and A. fumigatus may trigger different immune responses and exhibit different susceptibilities to macrophage mediated killing. We compared the transcriptomic and inflammatory profiles of human macrophages challenged with S. apiospermum (Sap) or A. fumigatus (Afu) for 4 h and 12 h, and assessed fungal survival. Sap activated multiple pro-inflammatory pathways, overlapping with those induced by Afu. At 4 h, 15 inflammation-related pathways were differentially regulated in Sap-infected macrophages (FDR 4 × 10^-2 to 7 × 10^-13), 12 of which were also upregulated in Afu-infected cells. The most highly dysregulated pathways involved TNF, IL-17, NF-κB signaling, and cytokine-cytokine receptor interactions. Sap induced a stronger, earlier inflammatory response, with three times more genes upregulated at 4 h than for Afu (671 vs. 200), and significantly higher levels of IL-6, IL-1β, TNF-α, IL-23, IL-10 (p <0.001), and IFN-α2 (p <0.05) secretion. The proportions of macrophages infected at 4 h were similar for the two fungi, but Sap conidia were more efficiently killed after 6 h (46.6% vs. 34.5%, p <0.05). Thus, S. apiospermum elicits a faster and stronger inflammatory macrophage response than A. fumigatus, potentially enhancing fungal clearance but also exacerbating airway inflammation in CF.