Recentin vitroandin vivostudies suggest that epigenetic training in innate immune cells can alter cellular function over extended time periods. It is unclear to what extent such training persists in human myeloid cells during microbial infections and alters clinical outcomes. We therefore examined longitudinal transcriptional and epigenetic changes in patients with Cystic Fibrosis (CF), a disease characterised by temporal fluctuations in lung infection and inflammation. We find that sudden clinical deteriorations in lung health, termed Acute Pulmonary Exacerbations (APEs), are linked to a robust innate immune response (triggered in part by pattern recognition receptor (PRR) activation) and associated changes in phagocytic function. Treatment of patients with intravenous antibiotics results in rapid modification of myeloid cell gene expression and epigenetic state, towards that of healthy volunteers, and suggests that CF inflammatory lung damage is driven by repeated acute inflammatory episodes rather than a distinct chronic inflammatory programme.
