Evaluation of antifungal drugs by an invasive aspergillosis-on-chip model

Author:

S Hartung1,2*, TNM Hoang1,2*, Z Cseresnyes3*, N Schuck1, K Rennert4,5, F Klos6, AS Mosig5,7, MT Figge3,8, M von Lilienfeld-Toal1,2

* Authors 1, 2 and 3 contributed equally

Author address:

1Infections in Hematology / Oncology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany

2Hematology and Medical Oncology, Jena University Hospital, Jena, Germany

3Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany

4Dynamic 42 GmbH, Jena, Germany

5Inspire, Jena University Hospital, Jena, Germany

6Transfer Group Anti-Infectives, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany

7Institute of Biochemistry II, Jena University Hospital, Jena, Germany

8Institute of Microbiology, University of Jena, Jena, Germany

Full conference title:

10th Advances Against Aspergillosis and Mucormycosis

Date: 2 February 2022

Abstract:

Purpose:

Invasive fungal infections by the mould Aspergillus fumigatus in immunocompromised patients are significantly increasing. Infection occurs in the lung where fungal conidia germinate to grow into filamentous bodies (hyphae), penetrate the epithelium and invade into the bloodstream. Invasive aspergillosis is associated with high mortality rates and limited treatment options. Testing of new antifungal drugs in vitro is insufficient, making animal models the gold-standard for drug efficacy testing. To overcome in vitro limitations, organ-on-chip systems mimic human physiology much more closely, thus providing a more suitable drug testing environment in terms of organ structure, cell types and dynamics (e.g. flow). Here, we used our recently established “invasive aspergillosis-on-chip” (IAC) model to re-capitulate the treatment of A. fumigatus infection by the well-established drugs Voriconazole (VOR) and Caspofungin (CAS) as well as the potentially new antifungal agent Jagaricin (JAG).

 

Methods:

The microfluidic IAC models, including human alveolar epithelial cells at an air-liquid-interface and perfused human endothelial cells separated by a porous membrane, were infected with A. fumigatus conidia and treated with drugs over night. While clinically relevant concentrations were used for VOR, CAS and JAG were subjected to dose-response curves. Advanced automated image analysis of three-dimensional confocal microscopy images of the models allowed us to quantify hyphal horizontal and vertical (invasive) growth and branching behaviour.

 

Results:

The fungicidal agent VOR was able to eradicate the fungus completely as no fungus was found in IAC models in contrast to extended hyphal networks in untreated controls. Fungistatic CAS stalled fungal growth and caused known morphological changes at increasing concentrations. A significant reduction in hyphae horizontal length was observed for 0.5µg/ml CAS in comparison to untreated controls but also to 5µg/ml CAS (“paradoxical growth”). More importantly, CAS-treated

endothelium of the IAC model. Again, invasive growth was lowest for 0.5µg/ml CAS. JAG compromised the epithelium and led to cell layer destruction at increasing concentrations.

 

Conclusion:

The clinically applied antifungal agents VOR and CAS performed in the IAC models as expected. However, the presence of invasive hyphae in CAS-treated samples, not detected in previous tests that only look at horizontal growth, highlight the necessity of in vivo-like test systems. In long run, organ-on-chip models may provide a much-needed tool to overcome animal testing.

Abstract Number: 84

Conference Year: 2022

Link to conference website: https://aaam2022.org/

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