Abstract
BACKGROUND: Staphylococcus aureus is the most common pathogen causing skin and soft-tissue infection and poses a particular problem to patients with atopic dermatitis who have increased colonization and infection rates. S. aureus is a versatile pathogen that adapts to the relatively hypoxic environment of the skin, although the underlying mechanisms of adaptation remain unclear. We hypothesized that adaptation to the skin is largely driven by metabolic interactions between S. aureus and keratinocytes. METHODS: We characterized 10 clinical S. aureus isolates obtained from individual patients with atopic dermatitis using whole genome sequencing and qRT-PCR to evaluate their genotypic and phenotypic properties. The metabolic and inflammatory responses of keratinocytes to S. aureus infection were assessed in vitro in primary human keratinocytes and in vivo in a murine cutaneous abscess model. RESULTS: Host-adapted S. aureus isolates from atopic dermatitis patients are phylogenetically diverse and are associated with varying severity of disease. They stimulate glycolysis and stabilize HIF1α in keratinocytes, and produce a similar infectious phenotype to WT USA300 LAC in a murine cutaneous abscess model. Numerous metabolic nonsynonymous mutations in genes encoding glycolytic and TCA cycle enzymes were identified in these strains. Increased expression of fumC, that encodes fumarase which hydrates fumarate to malate in the TCA cycle, was observed in the clinical isolates compared with WT LAC. Based on this finding and recent literature demonstrating that fumarate accumulation in immune cells is vital for trained immunity and that it inhibits glycolysis via GAPDH inactivation, we hypothesized that host-adapted S. aureus strains upregulate fumarase in response to increased fumarate levels in the skin. Keratinocytes infected with our clinical strains secrete increased fumarate compared with uninfected keratinocytes. CONCLUSION: S. aureus strains from atopic dermatitis skin represent a diverse population that are unified in their ability to adapt via metabolic interactions with keratinocytes. They adapt to increased fumarate levels in the skin by upregulating fumarase which likely represents a feedback inhibitory response to increased glycolysis in keratinocytes. DISCLOSURES: All authors: No reported disclosures.