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Updated: Apr 6, 2026
A Controlled Mouse Model for Neonatal Polymicrobial Sepsis
Published on: January 27, 2019
Building a better neonatal mouse model to understand infant respiratory syncytial virus disease
Dahui You1,2, David T Siefker1,2, Bishwas Shrestha1,2
1Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA.
Insights
A new chimeric virus, rA2-19F, causes more severe respiratory syncytial virus (RSV) lung disease in infant mice than the standard A2 strain. This enhanced model better mimics human infant RSV infections, aiding research into treatments.
Area of Science:
- Virology
- Immunology
- Pathology
Background:
- Respiratory syncytial virus (RSV) is a leading cause of infant respiratory infections.
- Severe RSV infection is linked to childhood asthma development.
- Current treatments for RSV are limited, and pathogenesis mechanisms in infants are unclear.
Purpose of the Study:
- To develop a more effective neonatal mouse model for studying RSV infection.
- To evaluate a chimeric RSV strain (rA2-19F) with an altered F protein for improved pathogenicity in neonates.
Main Methods:
- Neonatal mice were infected with either the standard A2 strain or the chimeric rA2-19F strain.
- Lung pathology, immune cell responses (T cells), cytokine profiles, and viral load were assessed.
- A subset of mice underwent primary infection, maturation, and subsequent reinfection to evaluate long-term immune responses and disease severity.
Main Results:
- The rA2-19F strain induced significantly greater lung pathology, including inflammation and mucus production, compared to the A2 strain.
- rA2-19F infection led to a pronounced Th2 immune response and reduced Th1/CD8+ T cell activity.
- Reinfection with rA2-19F exacerbated these responses, resulting in increased airway hyperreactivity and mucus production.
Conclusions:
- The rA2-19F strain provides a more robust neonatal mouse model for RSV infection due to its enhanced lung pathology and distinct immune response profile.
- The observed pathology is associated with higher viral loads and a shift towards Th2 immunity.
- This improved model can facilitate research into RSV pathogenesis and the development of novel therapies.
Background:
Respiratory syncytial virus (RSV) is the number one cause of lower respiratory tract infection in infants; and severe RSV infection in infants is associated with asthma development. Today, there are still no vaccines or specific antiviral therapies against RSV. The mechanisms of RSV pathogenesis in infants remain elusive. This is partly due to the fact that the largely-used mouse model is semi-permissive for RSV. The present study sought to determine if a better neonatal mouse model of RSV infection could be obtained using a chimeric virus in which the F protein of A2 strain was replaced with the F protein from the line 19 clinical isolate (rA2-19F).
Methods:
Five-day-old pups were infected with the standard laboratory strain A2 or rA2-19F and various immunological and pathophysiological parameters were measured at different time points post infection, including lung histology, bronchoalveolar lavage fluid (BALF) cellularity and cytokines, pulmonary T cell profile, and lung viral load. A cohort of infected neonates were allowed to mature to adulthood and reinfected. Pulmonary function, BALF cellularity and cytokines, and T cell profiles were measured at 6 days post reinfection.
Results:
The rA2-19F strain in neonatal mice caused substantial lung pathology including interstitial inflammation and airway mucus production, while A2 caused minimal inflammation and mucus production. Pulmonary inflammation was characterized by enhanced Th2 and reduced Th1 and effector CD8(+) T cells compared to A2. As with primary infection, reinfection with rA2-19F induced similar but exaggerated Th2 and reduced Th1 and effector CD8(+) T cell responses. These immune responses were associated with increased airway hyperreactivity, mucus hyperproduction and eosinophilia that was greater than that observed with A2 reinfection. Pulmonary viral load during primary infection was higher with rA2-19F than A2.
Conclusions:
Therefore, rA2-19F caused enhanced lung pathology and Th2 and reduced effector CD8(+) T cell responses compared to A2 during initial infection in neonatal mice and these responses were exacerbated upon reinfection. The exact mechanism is unknown but appears to be associated with increased pulmonary viral load in rA2-19F vs. A2 infected neonatal lungs. The rA2-19F strain represents a better neonatal mouse model of RSV infection.
