Invasive aspergillosis-on-chip: A quantitative treatment study of human Aspergillus fumigatus infection

Invasive pulmonary aspergillosis is associated with a high mortality rate and poses a direct threat to immunocompromised patients. Here, we present the invasive aspergillosis-on-chip (IAC) model to investigate Aspergillus fumigatus infection in vitro. The model allows the study of the lateral growth and the invasive behaviour of fungal hyphae from the epithelium into the endothelial cell layer in an alveolus-on-chip model. We established an algorithm-based analysis pipeline for three-dimensional confocal microscopy images to visualize and quantify fungal morphology, including hyphal growth and branching. Human macrophages in the IAC model partially inhibited the growth of the fungus, contributed to the release of proinflammatory cytokines (IL-1, IL-6, TNF) and chemokines (IL-8 and MCP-1) associated with an increased number of invasive hyphae. Similar to in vivo, the application of the fungistatic drug caspofungin limited the fungal growth and resulted in morphological changes of the hyphal tree previously described in other studies. The IAC infection model allows the identification and characterization of cellular infection targets and in vitro testing of antifungal drugs in clinically relevant concentrations. It thus represents a promising tool to broaden the understanding of pathogenicity and pathophysiology of invasive aspergillosis.

Automated summary

Invasive pulmonary aspergillosis is a serious infection with a high mortality rate. The invasive aspergillosis-on-chip (IAC) model allows the study of fungal growth and invasion in vitro. The model uses an algorithm-based analysis pipeline to visualize and quantify the morphology of the fungus. Macrophages in the IAC model inhibit fungal growth partially and contribute to the release of proinflammatory cytokines and chemokines. The fungistatic drug caspofungin limits fungal growth and causes morphological changes in the hyphal tree.