Pulmonary immunity is impaired in early life and by certain respiratory diseases such as chronic obstructive pulmonary disease, resulting in more severe infection and prolonged pulmonary dysfunction. We have established an early-life model of Chlamydia respiratory infection that drives immune responses leading to the development of emphysema and impaired lung function. Using this model we have demonstrated pivotal roles for novel immune factors such as toll-like receptor 2 (TLR2), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interleukin-13 (IL-13). All these factors were induced by infection and genetic deletion of these factors protected against impaired lung function in later-life. We are investigating the mechanisms involved. We propose that a novel TLR2, TRAIL, IL-13 immune axis promotes long-term alterations in lung function.
We have also established an experimental mouse model of cigarette smoke-induced COPD and superimposed this with a model of influenza infection. Using this model we have shown that COPD increased the severity of influenza infection and infection-induced inflammation. This was associated with reduced anti-viral responses. We show that PI3K activity is increased in COPD, which is utilized by influenza to induce a more severe infection. Importantly, inhibition of PI3K restored anti-viral responses. We also performed in vitro studies with human primary bronchial epithelial cells and identified the p110α as the PI3K isoform responsible for impaired anti-viral responses.
In summary, these studies identify a novel TLR2/TRAIL/IL-13 immune axis in early life bacterial infections and PI3K as a key mediator of anti-viral immune responses to influenza infection.