Immune response and clinical severity are shaped by skin-adapted <i>Staphylococcus aureus</i> in chronically infected patients.

Abstract

Despite the well-described association of skin lesions with <i>Staphylococcus aureus</i>, the distinct ability of clinical isolates to influence the local and systemic inflammatory response in a patient-specific manner is insufficiently characterized. In this study, we analyzed clinical recessive dystrophic epidermolysis bullosa (RDEB), which is characterized by wounds chronically colonized with <i>S. aureus</i>, to explore the relationship between inflammatory immune response and strain diversity. Children with RDEB (moderate phenotype, <i>n</i> = 5; severe phenotype, <i>n</i> = 10) and controls (<i>n</i> = 18) were enrolled in the study. Profiling of plasma proteins (<i>n</i> = 800), immune cells (<i>n</i> = 30 subsets and cytokine-producing cells), and cytokines (<i>n</i> = 38) identified a specific inflammatory signature in severe disease. Furthermore, patients with severe RDEB presented a high frequency of interleukin-17A+ (IL-17A+) cells among CD4+ and mucosal-associated invariant T (MAIT) lymphocytes. Positive <i>S. aureus</i> cultures from the skin of patients with RDEB allowed whole-genome sequencing of patient strains and assessment of primary keratinocyte immune response upon bacterial challenge. <i>S. aureus</i> secretome and conditioned medium from keratinocytes challenged with <i>S. aureus</i> strains from patients with severe but not from those with moderate RDEB promoted strong activation and a pro-IL-17 response in both CD4+ and MAIT cells. Our findings show that <i>S. aureus</i> strains isolated from patients with severe RDEB induce an IL-17-skewed immune response and pave the way for precision microbiology to explain and predict the highly variable virulence potential of bacterial clinical isolates.