Abstract
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.
Author summary Staphylococcus aureus is a well-known human pathogen causing both benign and life-threatening infections. Strinkingly, S. aureus has the ability to persist in the lungs of patients suffering from chronic respiratory disease for several years despite antibiotic therapies. Such a long-term persistence relies on a continuous within-host adaptation over time to cope with environmental pressures encountered in the lungs. In this study, we identified important genomic, proteomic and metabolic changes occurring during within-lungs adaptation of S. aureus. The pathways and virulence factors identified in this study as possibly leading to persistence may constitute novel therapeutic targets.