Longitudinal multimodal imaging-compatible mouse model of triazole-sensitive and -resistant invasive pulmonary
Agustin Resendiz-Sharpe1, Roberta Peres da Silva2, Elena Geib2
1Laboratory of Clinical Microbiology, Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit (KU) Leuven, 3000 Leuven, Belgium.
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.
Insights
Researchers developed an improved mouse model for studying invasive pulmonary aspergillosis (IPA). This model enhances imaging of fungal infections, aiding the development of new treatments for Aspergillus fumigatus, including drug-resistant strains.
Area of Science:
- Mycology
- Infectious Diseases
- Medical Imaging
Background:
- Invasive pulmonary aspergillosis (IPA) is a severe, life-threatening fungal infection, primarily affecting immunocompromised individuals.
- Increasing resistance of Aspergillus fumigatus to standard antifungal therapies necessitates advanced research models.
- Current models often lack the sensitivity and reproducibility required for comprehensive therapeutic evaluation.
Purpose of the Study:
- To systematically optimize a longitudinal, multimodal imaging-compatible neutropenic mouse model for invasive pulmonary aspergillosis (IPA).
- To enhance the detection sensitivity of fungal burden using in vivo bioluminescence imaging.
- To establish a platform for evaluating antifungal therapies against both susceptible and resistant strains of Aspergillus fumigatus.
Main Methods:
- Optimized a neutropenic mouse model using cyclophosphamide and orotracheal inoculation for reproducible IPA.
- Engineered red-shifted bioluminescent Aspergillus fumigatus strains (wild type and triazole-resistant mutants).
- Enhanced in vivo bioluminescence imaging sensitivity through optimized luciferin dosing and strain engineering.
- Validated the model by testing antifungal treatment scenarios based on in vitro susceptibility.
Main Results:
- Achieved reproducible rates of pulmonary infection in both male and female mice.
- Enabled early detection of fungal burden as early as one day post-infection using optimized bioluminescence imaging.
- Successfully demonstrated the utility of the model in evaluating both appropriate and inappropriate antifungal treatments in vivo.
Conclusions:
- Developed a novel, optimized neutropenic mouse model for studying invasive pulmonary aspergillosis.
- Integrated sensitive bioluminescence imaging for real-time monitoring of fungal infections.
- Provided a valuable platform for investigating the development and therapeutic strategies for both triazole-susceptible and triazole-resistant Aspergillus fumigatus infections.
