Investigation of the mechanisms of respiratory infection-induced lung disease

Chlamydia respiratory infections have been widely linked with the development and exacerbation of asthma, particularly more severe forms of asthma, in both children and adults. Murine models of Chlamydia respiratory infection and AAD were used to investigate the mechanisms that underpin the association between infection and asthma. We have made important and novel observations that demonstrate how neonatal Chlamydia infection results in chronic lung disease. We show that neonatal Chlamydia infection induces a group of 5 miRNAs (miR-155, miR-21, miR-223, miR-146b and miR-203) during infection and that the therapeutic inhibition of each miRNA can prevent the development of key disease features, including lung inflammation and histopathology, persistent AHR, emphysema-like alveolar enlargement and increased severity of AAD in later life. We have also made important and novel observations that further our understanding of the mechanisms that underpin the association between Chlamydia respiratory infection and severe, steroid-insensitive asthma. We demonstrate that Chlamydia respiratory infection in established AAD induces a miR-21/PI3K/pAkt/HDAC2 signalling axis to promote severe, steroid-insensitive AAD. Importantly, the therapeutic inhibition of Chlamydia-induced miR-21 and/or PI3K signalling restores sensitivity to steroid treatment. Additionally, the therapeutic inhibition of miR-21 also suppresses the key features of Haemophilus respiratory infection-induced, severe, steroid-insensitive AAD. We also demonstrate that Chlamydia respiratory infection induces an NLRP3 inflammasome/Caspase-1/IL-1β signalling axis to promote severe, steroid-insensitive AAD. Importantly, the therapeutic inhibition of Chlamydia-induced NLRP3 inflammasome and/or Caspase-1 and/or IL-1β signalling restores sensitivity to steroid treatment. Furthermore, the therapeutic inhibition of each component of this axis also suppresses the key features of Haemophilus respiratory infection-induced, severe, steroid-insensitive AAD. Our studies significantly contribute to understanding the role of neonatal Chlamydia respiratory infection in the development of chronic lung disease and severe asthma in later life, and the roles of Chlamydia and Haemophilus respiratory infections in promoting severe, steroid-insensitive asthma. Importantly, our studies suggest that therapeutically targeting key Chlamydia and Haemophilus respiratory infection-induced factors in the lung may be effective for the prevention and/or treatment of severe asthma.