Signaling sphingolipids are biomarkers for atopic dermatitis prone to disseminated viral infections

Background: Life-threatening viral diseases such as eczema herpeticum (EH) and eczema vaccinatum (EV) occur in <5% of individuals with atopic dermatitis (AD). The diagnosis of AD, however, excludes all individuals with AD from smallpox vaccination. Objectives: We sought to identify circulatory and skin lipid biomarkers associated with EH and EV. Objectives: We sought to identify circulatory and skin lipid biomarkers associated with EH and EV. Methods: Stratum corneum and plasma samples from 15 subjects with AD and a history of EH, 13 age- and gender--matched subjects with AD and without EH history, and 13 healthy nonatopic (NA) controls were analyzed by liquid chromatography tandem mass spectrometry for sphingolipid content. Sphingosine-l-phosphate (S1P) and ceramide levels were validated in plasma samples from the Atopic Dermatitis Vaccinia Network/Atopic Dermatitis Research Network repository (12 NA, 12 AD, 23 EH) and plasma from 7 subjects with EV and 7 matched subjects with AD. SlP lyase was downregulated in human primary keratinocytes to evaluate its effect on herpes simplex virus 1 (HSV-1) replication in vitro. Results: The stratum corneum of patients with EH demonstrated significantly higher levels of free sphingoid bases than those in patients who were NA, indicating enhanced sphingolipid turnover in keratinocytes (P < .05). Plasma from 2 independent cohorts of patients with EH had a significantly increased S1P/ceramide ratio in subjects with EH versus those with AD and or who were NA (P < .01). The SW level in plasma from subjects with EV was twice the level in plasma from subjects with AD (mean = 1,533 vs 732 pmol/mL; P < .001). Downregulation of SlP lyase expression with silencing RNA led to an increased SlP level and doubled HSV-1 titer in keratinocytes. Conclusions: Our data point to long-term abnormalities in the SW signaling system as a biomarker for previous disseminated viral diseases and a potential treatment target in recurring infections.

Automated summary

This study identified enhanced sphingolipid turnover in the stratum corneum of patients with eczema herpeticum (EH), an increased S1P/ceramide ratio in EH patients' plasma, and elevated SW levels in the plasma of patients with eczema vaccinatum (EV). Downregulation of S1P lyase expression resulted in increased S1P levels and doubled herpes simplex virus 1 (HSV-1) titer in keratinocytes. These findings suggest that the SW signaling system may serve as a biomarker for previous disseminated viral diseases and a potential treatment target in recurring infections.