Abstract
There is emerging epidemiological data to suggest that upper respiratory tract bacterial colonisation in infancy may increase the risk of developing respiratory dysfunction later in life, and respiratory viruses are known to precipitate persistent colonisation. This study utilized a neonatal mouse model of Streptococcus pneumonia (SP) and influenza A virus (IAV) co-infection, where bronchoalveolar leukocyte infiltration had resolved by adulthood. Only co-infection resulted in persistent nasopharyngeal colonisation over 40 days and a significant increase in airway resistance in response to in vivo methacholine challenge. A significant increase in hysteresivity was also observed in IAV and co-infected mice, consistent with ventilatory heterogeneity and structural changes in the adult lung. Airway hyper-responsiveness was not associated with a detectable increase in goblet cell transdifferentiation, peribronchial smooth muscle bulk or collagen deposition in regions surrounding the airways. Increased reactivity was not observed in precision cut lung slices challenged with methacholine in vitro. Histologically, the airway epithelium appeared normal and expression of epithelial integrity markers (ZO-1, occludin-1 and E-cadherin) were not altered. In summary, neonatal co-infection led to persistent nasopharyngeal colonisation and increased airway responsiveness that was not associated with detectable smooth muscle or mucosal epithelial abnormalities, however increased hysteresivity may reflect ventilation heterogeneity.
Highlights
Influenza-associated hospitalization rates in children younger than 5 years old are exceeded only by the elderly[1]
A significant increase in central airways resistance in response to MCh challenge was only observed in adult mice co-infected with Streptocococcus pneuemoniae (SP) and influenza A virus (IAV) during infancy, in contrast to mice infected with a single respiratory pathogen
Residual lung function defects in adulthood were observed in mice that were challenged with IAV in infancy[14]
Summary
Influenza-associated hospitalization rates in children younger than 5 years old are exceeded only by the elderly[1]. The detection of bacteria that can colonise the airways occurs frequently during significant bronchiolitis episodes; the common terminology of viral wheeze may not accurately reflect the aetiological nature of many acute events in children under the age of 5 years[8,9]. It has been established that influenza and other viruses can acutely alter lung function and lead to airway hyper-responsiveness (AHR) in response to increasing concentrations of constrictor agonists, such as methacholine (MCh)[12]. In contrast to adult mice, physiological and inflammatory responses to IAV infection were assessed in infant mice, where residual AHR persisted for 21 days when inflammation and alveolar–capillary permeability had fully resolved[14]. The effect of infant co-infection with SP and IAV on adult mouse lung function was assessed, revealing persistence of MCh-induced hyper-responsiveness that was independent of mucosal epithelial abnormalities
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