IMMUNOPATHOLOGICAL RESPONSE TO PSEUDOMONAS AERUGINOSA AND POTENTIAL THERAPIES IN RESPIRATORY INFECTIONS

Repeated cycles of infections, caused mainly by Pseudomonas aeruginosa, combined with a robust host immune response and tissue injury, determine the course and outcome of cystic fibrosis (CF) lung disease. The initial acute infection disease is kept in check by an excessive neutrophildominated inflammation, while as the disease progresses P. aeruginosa adapts to the airways and dramatically modifies its phenotype causing permanent chronic infection. The persistent P. aeruginosa infection escapes the innate immune responses and causes damage to the host. Airways remodelling is characterized by mucus hypersecretion, degradation of its structural components, caused by the activity of matrix metalloproteinases, and high level of sulphated glycosaminoglycans (GAG). However, whether, how and at to what extent bacterial adaptive variants and their persistence influence the pathogenesis and disease development, and the role played by GAG in this context remain largely unknown. Using in vitro and murine models of acute and chronic lung infection, we showed that P. aeruginosa CF‐adaptive variants shaped the innate immune response favoring their persistence. Next, we refined a murine model of chronic pneumonia extending P. aeruginosa infection up to three months. In this model we observed that the P. aeruginosa persistence lead to CF hallmarks of airway structural degeneration and fibrosis, including epithelial hyperplasia, goblet cell metaplasia, collagen deposition, elastin degradation, GAG remodelling and several additional markers of tissue damage. This murine model was further exploited to test the effect of a library of compounds that could compete with GAG present in the lung (GAG mimetics), with attenuated anticoagulant properties, on host response to P. aeruginosa infection. GAG mimetics C3 and C23 demonstrated a remarkable efficacy in reducing inflammation and tissue damage. These molecules contained also the bacterial load during P. aeruginosa chronic infection, probably acting on biofilm formation. Overall, the murine model of P. aeruginosa chronic infection, reproducing CF lung pathology, established in this work has been instrumental to identify novel molecular targets and to test newly tailored molecules inhibiting chronic inflammation and tissue damage processes in pre‐clinical studies. In addition, the results obtained with GAG mimetics support the developments of these compounds as novel therapy in CF and potentially for the treatment of other chronic respiratory pathologies.