Non-viable <i>Aspergillus fumigatus</i> promotes chronic inflammation and angiogenesis in a murine fungus ball model

An aspergilloma is a fungus ball that forms within a preexisting cavity, most commonly in the lungs but also in the paranasal sinuses. It represents a chronic inflammatory disorder that can persist for months and cause life-threatening hemoptysis. In this study, we hypothesized that the fungus ball is predominantly composed of non-viable hyphae and that chronic inflammation is maintained primarily by host responses to these non-viable elements rather than by ongoing fungal proliferation. To investigate this, we created a murine fungus ball model by implanting heat-killed <i>Aspergillus fumigatus</i> fungus balls, allowing for ≥16 weeks of longitudinal assessment. The model recapitulated key pathological features of the human disease, including progressive fibrosis and sustained angiogenesis, coinciding with elevated vascular endothelial growth factor (VEGF). A distinct immune response was observed where neutrophils infiltrated the fungus ball core, while macrophages accumulated at the periphery. Strikingly, these macrophages surrounding the lesion progressively became lipid-laden foam-like cells with an M1-skewed profile, a phenomenon reproduced <i>in vitro</i> by exposure to non-viable hyphae alone. Thus, the fungal material itself can sustain chronic inflammation and vascular remodeling, implicating macrophage lipid accumulation as a process potentially contributing to the chronic host response. These findings highlight lipid dysregulation and failed fungal clearance as key features of the host-response disorder associated with the fungus ball and establish a tractable platform for evaluating host-directed therapies.IMPORTANCEAspergilloma, a fungus ball that forms in preexisting cavities of the lung or paranasal sinuses, can cause chronic symptoms and life-threatening bleeding. Current fungicidal treatments, including antifungals, are often ineffective, and surgery to remove the fungal ball is risky. To better understand why these lesions can persist even when active fungal growth is limited, we developed a murine subcutaneous fungus ball model using non-viable <i>Aspergillus fumigatus</i>. In this model, a fungal mass composed largely of non-viable hyphae was associated with chronic inflammation, neovascularization, fibrosis, and the accumulation of lipid-laden, foam cell-like macrophages around the fungus ball. These findings support the concept that persistent non-viable fungal material can sustain key features of aspergilloma-like pathology through dysregulated host responses. They provide a conceptual rationale for future studies of host-directed strategies that modulate inflammatory and lipid-handling pathways in addition to conventional antifungal approaches.