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Published on: June 25, 2015
Rapid generation of a murine RSV infectious model by transducing a conditional knock-in mouse harboring human IGF1
Rui Xiong1, Yong Wu2, Yuya Wang2
1Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control (NIFDC), National Rodent Laboratory Animal Resources Center, Beijing, China.
Insights
A new mouse model expressing human insulin-like growth factor 1 receptor (hIGF1R) in the lungs effectively mimics severe pediatric respiratory syncytial virus (RSV) disease. This model aids in evaluating RSV vaccines and antiviral drugs.
Area of Science:
- Virology and Immunology
- Animal Models for Infectious Diseases
- Vaccine Development
Background:
- Human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants.
- Current animal models do not fully replicate pediatric RSV susceptibility, hindering vaccine and therapeutic development.
- The human insulin-like growth factor 1 receptor (hIGF1R) is identified as a key host receptor for RSV entry.
Purpose of the Study:
- To develop a pediatric-relevant mouse model for studying respiratory syncytial virus (RSV) infection.
- To assess the utility of a novel mouse model expressing lung-specific hIGF1R for evaluating RSV countermeasures.
Main Methods:
- Generation of a conditional knock-in mouse model with lung-specific hIGF1R expression via Ad5 vector transduction.
- Intranasal challenge of four-week-old Ad5-hIGF1R mice with RSV A2.
- Analysis of pulmonary viral loads, lung pathology, and gene expression (chemokines).
- Evaluation of a prefusion F (pre-F) vaccine regimen in the Ad5-hIGF1R mouse model.
Main Results:
- Ad5-hIGF1R mice exhibited significantly higher viral loads and severe lung inflammation, mimicking pediatric RSV disease.
- Transcriptomic analysis identified 12 upregulated chemokine genes associated with immune responses, potential biomarkers for RSV.
- Pre-F vaccination reduced viral loads and lung neutrophil infiltration in the Ad5-hIGF1R model.
Conclusions:
- Lung-specific hIGF1R expression enhances RSV replication and immunopathology in young mice.
- The Ad5-hIGF1R mouse model overcomes limitations of conventional models, offering a valuable platform for RSV vaccine and drug assessment.
- This model provides a promising avenue for advancing RSV prevention strategies.
Abstract:
Human respiratory syncytial virus (RSV) remains the leading viral cause of severe lower respiratory tract disease in infants and young children worldwide. Despite decades of research, RSV vaccine development remains hindered by the lack of animal models that accurately recapitulate pediatric susceptibility and allow rigorous assessment of protective efficacy and safety. Recent studies have identified the human insulin-like growth factor 1 receptor (hIGF1R) as a critical host receptor that facilitates RSV fusion and entry. Using a novel conditional knock-in mouse model, lung-specific hIGF1R expression achieved through Ad5 vector transduction enables rapid generation of a pediatric-relevant mouse model, offering a promising route to close this gap. Following intranasal challenge with RSV A2 (1.62 × 105 TCID50), four-week-old Ad5-hIGF1R mice exhibited higher pulmonary viral loads, marked peribronchiolar and perivascular inflammation, interstitial thickening and a tendency toward alveolar wall coalescence compared with wild-type controls, thereby recapitulating severe pediatric RSV disease. Transcriptomic analysis revealed 12 chemokine genes, upregulated in RSV-infected lungs of Ad5-hIGF1R mice relative to mock controls, that are involved in immune-inflammatory pathways and may serve as practical biomarkers for detecting dysregulated host responses during vaccine or antiviral-drug assessment. Furthermore, A mid-dose prefusion F (pre-F) vaccination regimen significantly reduced viral loads and moderately attenuated neutrophil infiltration in the lungs of Ad5-hIGF1R mice. In summary, the young Ad5-hIGF1R mice demonstrate that hIGF1R expression enhances RSV replication and immunopathology in vivo. This model not only overcomes the limited RSV susceptibility of conventional young mice but also provides a platform for evaluating RSV vaccines.
