Lipid Profiles in Eczema Herpeticum and Eczema Vaccinatum Reflect Changes that Predispose to Disseminated Viral Infection

Atopic dermatitis (AD) is the most common inflammatory skin disease. Less than 5% of AD is complicated by eczema herpeticum (EH) and eczema vaccinatum (EV) but this has led to the CDC recommendation that all AD should not receive smallpox vaccination. Biomarkers of susceptibility to EH and EV are not known. Stratum corneum and plasma samples from 15 AD subjects with a history of EH (ADEH+), 13 age- and gender- matched AD subjects without EH history (ADEH-), and 13 healthy controls (HC) were analyzed by liquid chromatography tandem mass spectrometry for sphingolipid content. Sphingosine-1-phosphate (S1P) and ceramide levels were also determined in plasma from seven EV subjects and seven matched AD subjects. S1P lyase was down-regulated in human primary keratinocytes to evaluate its effect on HSV-1 replication in vitro. Stratum corneum of ADEH+ demonstrated significantly higher levels of free sphingoid bases than HC indicating enhanced sphingolipid turnover in keratinocytes (p<0.05). Plasma of ADEH+ subjects had increased S1P/ceramide ratio versus HC (p<0.05) and ADEH-(P<0.01). S1P level in plasma from EV subjects was twice its level in ADEH- subjects (mean=1533 vs 732 pmol/ml, p<0.001). Downregulation of S1P lyase expression with siRNA increased S1P level and doubled HSV-1 titer in keratinocytes. Our data suggest the involvement of S1P-mediated signaling in HSV and VV replication and demonstrate that both EV and EH are associated with persistent changes in sphingolipid metabolism. Increased sphingoid bases and their phosphates in the skin and blood may be a biomarker for patients prone to disseminated viral infection.