A mouse model of childhood asthma: mechanisms of development and progression following an early-life respiratory viral infection

Background: Lower respiratory tract infections in childhood, including viruses such as respiratory syncytial virus (RSV), are strongly linked to development of allergic asthma. The aim of this project was to develop a mouse model of the induction phase of childhood asthma, to facilitate investigation of the interaction of early-life infection with RSV, subsequent allergen exposure and development of asthma, as well as the underlying mechanisms. Methods: BALB/c mice were neonatally infected with pneumonia virus of mice (PVM, which is a mouse-specific virus of the same family and genus as RSV). Following recovery, mice were intranasally sensitised with ovalbumin and challenged with a low level of aerosolised antigen for 4 weeks, followed by a single moderate-level challenge to trigger acute allergic inflammation. To assess underlying mechanisms, antibodies against IL-4 or IL-25, which contribute to induction of a Th2 response, were administered either during the chronic challenge period or in early life alone. Results: Development of an asthmatic phenotype (allergic airway inflammation, changes of remodelling and airway hyperresponsiveness (AHR)) required both recovery from neonatal infection and subsequent allergen sensitisation/challenge. By comparison, changes of remodelling were evident in mice that received allergen challenge alone, while development of AHR was associated with PVM infection alone. Signalling via the IL-4 receptor alpha chain was crucial to the development of allergic inflammation, goblet cell change and AHR, because these were absent in receptor-deficient mice. Administration of anti-IL-4 during chronic challenge inhibited allergic airway inflammation and goblet cell hyperplasia/metaplasia, but not other changes of remodelling. In contrast, anti-IL-25 selectively suppressed recruitment of eosinophils, but not of neutrophils. Anti-IL-25 also inhibited airway remodelling, but had no effect on goblet cells. Treatment with anti-IL-25 in early life had similar effects. Both antibodies suppressed development of a Th2 response, while anti-IL-25 promoted a Th17 response. Conclusion: In this murine model, interaction between early-life viral infection and allergen sensitisation/challenge is essential for development of changes typical of an asthmatic phenotype. Furthermore, suppressing the Th2 response, either during the neonatal period or later in childhood, prevents development of some of the key features of childhood asthma.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2011

Author dc:creator

• Siegle, Jessica Sarah

• Animal model
• Childhood asthma
• Th2 response

Statement dc:rights

• open access
• CC BY-NC-ND 3.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by-nc-nd/3.0/au/

Language dc:language

EN

Identifier

https://doi.org/10.26190/unsworks/23512

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/50331