Abstract

BackgroundEarly-life respiratory viral infections, notably with respiratory syncytial virus (RSV), increase the risk of subsequent development of childhood asthma. The purpose of this study was to assess whether early-life infection with a species-specific model of RSV and subsequent allergen exposure predisposed to the development of features of asthma.MethodsWe employed a unique combination of animal models in which BALB/c mice were neonatally infected with pneumonia virus of mice (PVM, which replicates severe RSV disease in human infants) and following recovery, were intranasally sensitised with ovalbumin. Animals received low-level challenge with aerosolised antigen for 4 weeks to elicit changes of chronic asthma, followed by a single moderate-level challenge to induce an exacerbation of inflammation. We then assessed airway inflammation, epithelial changes characteristic of remodelling, airway hyperresponsiveness (AHR) and host immunological responses.ResultsAllergic airway inflammation, including recruitment of eosinophils, was prominent only in animals that had recovered from neonatal infection with PVM and then been sensitised and chronically challenged with antigen. Furthermore, only these mice exhibited an augmented Th2-biased immune response, including elevated serum levels of anti-ovalbumin IgE and IgG1 as well as increased relative expression of Th2-associated cytokines IL-4, IL-5 and IL-13. By comparison, development of AHR and mucous cell change were associated with recovery from PVM infection, regardless of subsequent allergen challenge. Increased expression of IL-25, which could contribute to induction of a Th2 response, was demonstrable in the lung following PVM infection. Signalling via the IL-4 receptor α chain was crucial to the development of allergic inflammation, mucous cell change and AHR, because all of these were absent in receptor-deficient mice. In contrast, changes of remodelling were evident in mice that received chronic allergen challenge, regardless of neonatal PVM infection, and were not dependent on signalling via the IL-4 receptor.ConclusionIn this mouse model, interaction between early-life viral infection and allergen sensitisation/challenge is essential for development of the characteristic features of childhood asthma, including allergic inflammation and a Th2-biased immune response.

Highlights

  • Early-life respiratory viral infections, notably with respiratory syncytial virus (RSV), increase the risk of subsequent development of childhood asthma

  • Epidemiological studies strongly suggest that lower respiratory viral infections associated with wheezing, especially in early childhood, play an important role in the subsequent development of asthma in children who are repeatedly exposed to inhaled allergens [3,4,5,6,7,8]

  • Because RSV infection within the earliest months of life is most clearly related to subsequent development of asthma, and because previous studies have established that the pattern of host response to pneumovirus infection is age-dependent [33,34], we examined responses only in mice infected with pneumonia virus of mice (PVM) in the first two days of life

Read more

Summary

Introduction

Early-life respiratory viral infections, notably with respiratory syncytial virus (RSV), increase the risk of subsequent development of childhood asthma. The purpose of this study was to assess whether early-life infection with a species-specific model of RSV and subsequent allergen exposure predisposed to the development of features of asthma. In its full-blown form, PVM infection induces severe pulmonary inflammation with recruitment of neutrophils and marked oedema, resembling acute respiratory distress syndrome [14]. This is paralleled by marked respiratory dysfunction as assessed by whole body plethysmography, which is accompanied by local production of proinflammatory mediators including MIP-1a, MIP-2, MCP-1 and IFN-g [15]. MIP-1a and IFN-g are crucial to granulocyte recruitment [14,16]

Objectives
Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call