Analysis of chronic host-aspergilloma interactions using a novel mouse model

An aspergilloma is a fungus ball caused by chronic infection of Aspergillus species in a pre-existing cavity, such as a destroyed lung or the sinuses. Patients with pulmonary aspergilloma are at risk of sudden life-threatening hemoptysis. Antifungal therapy is administered to aspergilloma patients who are ineligible for surgery, but its efficacy is limited. Understanding the pathophysiology of aspergilloma is crucial for developing further treatment strategies. The mechanism behind the long-term host response to aspergilloma is poorly understood. We created a novel mouse model to analyze the host response to aspergilloma by implanting a fungus ball of Aspergillus fumigatus into an air-filled subcutaneous cavity. Our findings indicate that a live fungus ball led to tissue invasion, even in immunized mice. When a fungus ball consisting of dead hyphae was implanted, it persisted for over three months and induced pathological findings simulating human aspergilloma, including an inflammatory cell infiltration into the fungus ball and angiogenesis in the cavity wall. Dead fungus ball induced Th1 and Th17 inflammatory cytokines and vascular endothelial growth factor. Neutrophils infiltrated the inside of the fungus ball immediately after implantation, and macrophages surrounded it after a one-week delay. The macrophages around the fungus ball were swollen with phagocytosed fragments of dead hyphae and transformed into foam cells containing fat droplets. We also confirmed in vitro that macrophages were damaged and transformed into foam cells by direct contact with dead hyphae. This model holds promise to provide new insights into the fungal-host interaction during aspergillomas.