Longitudinal multimodal imaging-compatible mouse model of triazole-sensitive and -resistant invasive pulmonary aspergillosis

Resendiz-Sharpe, Agustin; da Silva, Roberta Peres; Geib, Elena; Vanderbeke, Lore; Seldeslachts, Laura; Hupko, Charlien; Brock, Matthias; Lagrou, Katrien; Vande Velde, Greetje

Abstract

Invasive pulmonary aspergillosis (IPA) caused by the mold Aspergillus fumigatus is one of the most important life-threatening infections in immunocompromised patients. The alarming increase of isolates resistant to the first-line recommended antifungal therapy urges more insights into triazole-resistant A. fumigatus infections. In this study, we systematically optimized a longitudinal multimodal imaging-compatible neutropenic mouse model of IPA. Reproducible rates of pulmonary infection were achieved through immunosuppression (sustained neutropenia) with 150 mg/kg cyclophosphamide at day -4, -1 and 2, and an orotracheal inoculation route in both sexes. Furthermore, increased sensitivity of in vivo bioluminescence imaging for fungal burden detection, as early as the day after infection, was achieved by optimizing luciferin dosing and through engineering isogenic red-shifted bioluminescent A. fumigatus strains, one wild type and two triazole-resistant mutants. We successfully tested appropriate and inappropriate antifungal treatment scenarios in vivo with our optimized multimodal imaging strategy, according to the in vitro susceptibility of our luminescent fungal strains. Therefore, we provide novel essential mouse models with sensitive imaging tools for investigating IPA development and therapy in triazole-susceptible and triazole-resistant scenarios.

Citation

Resendiz-Sharpe, A., da Silva, R. P., Geib, E., Vanderbeke, L., Seldeslachts, L., Hupko, C., …Vande Velde, G. (2022). Longitudinal multimodal imaging-compatible mouse model of triazole-sensitive and -resistant invasive pulmonary aspergillosis. Disease Models and Mechanisms, 15(3), Article dmm049165. https://doi.org/10.1242/dmm.049165

• Journal Article Type: Article
• Acceptance Date: Jan 9, 2022
• Online Publication Date: Mar 30, 2022
• Publication Date: Mar 1, 2022
• Deposit Date: Apr 3, 2022
• Publicly Available Date: Apr 5, 2022
• Journal: Disease Models and Mechanisms
• Print ISSN: 1754-8403
• Electronic ISSN: 1754-8411
• Publisher: Company of Biologists
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 3
• Article Number: dmm049165
• DOI: https://doi.org/10.1242/dmm.049165
• Keywords: Invasive bronchopulmonary aspergillosis, Antifungal resistance, Murine model, Bioluminescence imaging, Micro-CT
• Public URL: https://nottingham-repository.worktribe.com/output/7688362
• Publisher URL: https://journals.biologists.com/dmm/article/15/3/dmm049165/274857/Longitudinal-multimodal-imaging-compatible-mouse