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.