Lung-adapted Staphylococcus aureus isolates with dysfunctional agr system trigger a proinflammatory response.

Abstract

BACKGROUND Staphylococcus aureus (Sa) dominates the lung microbiota of Cystic Fibrosis (CF) children and persistent clones are able to establish chronic infection for years, having a direct deleterious impact on lung function. However, in this context, the exact contribution of Sa to the decline in respiratory function in CF children is not elucidated. METHODS To investigate the contribution of persistent S. aureus clones in CF disease, we undertook the analysis of sequential isogenic isolates recovered from 15 young CF patients. RESULTS Using an Air-Liquid infection model, we observed a strong correlation between Sa adaption in the lung (late isolates), low toxicity and pro-inflammatory cytokine secretion. Conversely, early isolates appeared to be highly cytotoxic but did not promote cytokine secretion. We found that cytokine secretion was dependent on Staphylococcal protein A (Spa), which was selectively expressed in late compared to early isolates as a consequence of dysfunctional agr quorum-sensing system. Finally, we demonstrated the involvement of TNF-α receptor 1 signaling in the inflammatory response of airway epithelial cells to these lung-adapted Sa isolates. CONCLUSION Our results suggest an unexpected direct role of bacterial lung adaptation in the progression of chronic lung disease by promoting a pro-inflammatory response through acquired agr dysfunction.