Development of alternative treatments for fungal infections is imperative with the rapid increase in antifungal resistance worldwide. Aspergillus spp. infection can modify the lung microenvironment and promote growth via oxalic acid release. In vitro, Cupriavidus oxalaticus was shown to degrade oxalic acid, thereby decreasing Aspergillus spp. growth. We aimed to optimize experimental models to demonstrate the potential of this biocontrol mechanism for clinical interventions.

BalbC/J mice were treated with cyclophosphamide and cortisone acetate followed by lung infection with A. fumigatus CEA10, colonization with C. oxalaticus, or a combination of both. Immune cell composition and hyphal development were evaluated in BALF and lung tissue after 72h. To investigate this process in a clinically relevant context, the same approach was applied on human-derived immortalized alveolar epithelial cells (^AXiAEC) cultured on ^AXlung-on-chip. Transepithelial electrical resistance, cell morphology, and oxalic acid levels were assessed.

We optimized an A. fumigatus infection dose leading to hyphal formation in the lungs but with minimal distress for the animals. Colonization with C. oxalaticus led to immune priming with negligible airway inflammation. C.oxalaticus exposure altered ^AXiAEC morphology and enhanced barrier integrity in vitro. Moreover, initial results indicate that C. oxalaticus colonization can control A. fumigatus infection development both in vivo and in vitro.

We successfully optimized clinically relevant experimental models to test the potential of biocontrol by environmental interference in the context of pulmonary aspergillosis. This is the first time that biocontrol bacteria are used to contain respiratory fungal infection.