Persistent Staphylococcus aureus infections in children with chronic lung disease: a multi-omics analysis of bacterial adaptation to define novel therapeutic approaches

Patients suffering from chronic lung diseases are abnormally colonized by many commensal and pathogenic bacterial species among which Staphylococcus aureus is the most commonly identified pathogen (prevalence in the lungs of cystic fibrosis (CF) patients greater than 70%). However, the mechanisms underlying the adaptation of S. aureus to the lung are poorly understood.To get further insights into the molecular mechanisms of S. aureus adaptation to the chronic immunocompromised lung environment, we selected four pairs of sequential S. aureus isolates from 3 patients with CF and a patient with defective IgG antibody production suffering from chronic lung diseases. We used a combination of genomic, proteomic and metabolomic approaches with functional assays for in-depth characterization of S. aureus long-term persistence during chronic lung infection.We demonstrate that chronic infection with S. aureus is related to the accumulation of genetic modifications inducing altered protein expression profiles and notable metabolic changes. These modifications are concordant with both patient-specific adaptation and convergent evolution of S. aureus isolates. We identified several metabolic pathways (e.g., pantothenate and fatty acids) and virulence regulators (encoded by agr and sae loci) that could constitute therapeutic targets. Importantly, we show that long-term S. aureus infection leads to an increased ability to form biofilm and to a prolonged intracellular survival. Importantly, the increased ability to persist intracellularly was confirmed for S. aureus isolates within the own patient epithelial cells.Our results strongly suggest that the intracellular environment might constitute an important niche of persistence and relapse necessitating adapted antibiotic treatments. Moreover, the multi-omics approach described in this study paves the way towards personalized medicine for the chronic infection management.