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

• Published in: Disease models & mechanisms Vol. 15; no. 3
• Main Authors: Resendiz-Sharpe, Agustin, da Silva, Roberta Peres, Geib, Elena, Vanderbeke, Lore, Seldeslachts, Laura, Hupko, Charlien, Brock, Matthias, Lagrou, Katrien, Vande Velde, Greetje
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.03.2022; The Company of Biologists
• Subjects: Animals; antifungal resistance; Aspergillosis; Aspergillosis - diagnostic imaging; Aspergillosis - drug therapy; Aspergillus fumigatus; bioluminescence imaging; Disease; Female; Fungal infections; Humans; invasive bronchopulmonary aspergillosis; Invasive Pulmonary Aspergillosis - diagnostic imaging; Invasive Pulmonary Aspergillosis - drug therapy; Male; Mice; micro-ct; Model Systems in Drug Discovery; Mortality; Multimodal Imaging; murine model; Mutation; Neutropenia; Patients; Resource; Triazoles - pharmacology; Triazoles - therapeutic use; Virulence; Antifungal resistance; Micro-CT; Bioluminescence imaging; Invasive bronchopulmonary aspergillosis; Murine model
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.049165

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.