There is a critical window of time in early-life where the lung is still maturing and is susceptible to respiratory infection. Indeed, severe respiratory infections in early-life are a risk factor for the development of chronic lung diseases, including asthma. The aim of this study was to identify the potential mechanisms involved using model systems.

Neonatal wild-type (WT), TLR2 deficient (^-/-), IL-13^-/-, MyD88^-/- and STAT6^-/- mice were infected with the natural mouse bacterial pathogen Chlamydia muridarum, as a model of severe respiratory tract bacterial infection in early-life. In some experiments WT mice were treated with miR-21 specific antagomirs, PI3K inhibitors, or relevant controls during early-life infection. The impact of targeting these specific immune molecules during early-life on infection-induced impairment of lung function and structure were assessed in later-life.

Neonatal Chlamydia respiratory infection increased TLR2, IL-13-receptor, miR-21 and PI3K expression and/or activity in the lung. TLR2 signalling induced IL-13-receptor expression, IL-13 signalling induced miR-21 expression and miR-21 increased PI3K activity. TLR2 signalling also increased IL-13⁺ ILC2s in the lung. TLR2^-/- and IL-13^-/- mice were protected against infection-induced airway hyperresponsiveness (AHR), but not emphysema-like alveolar enlargement. This TLR2/IL-13 mediated phenotype was independent of MyD88, but dependent on STAT6. Specific targeting of miR-21 prevented AHR but not emphysema. Pan-PI3K inhibition did not affect AHR, but protected against emphysema. Interestingly, early-life infection-induced AHR was steroid insensitive.

This study identifies a novel TLR2/IL-13/miR-21-dependent, but MyD88-independent signalling pathway that may be targeted for the prevention of the long-term deleterious effects of early-life bacterial infection on lung function and asthma in later-life.