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CERS1 is a Biomarker of Staphylococcus aureus Abundance and Atopic Dermatitis Severity.

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CERS1 is a Biomarker of Staphylococcus aureus Abundance and Atopic Dermatitis Severity. The Journal of allergy and clinical immunology Kenney, H. M., Yoshida, T., Berdyshev, E., Calatroni, A., Gill, S. R., Simpson, E. L., Lussier, S., Boguniewicz, M., Hata, T., Chiesa Fuxench, Z. C., De Benedetto, A., Ong, P. Y., Ko, J., Davidson, W., David, G., Schlievert, P. M., Leung, D. Y., Beck, L. A. 2024

Abstract

Atopic dermatitis (AD) is an inflammatory skin condition characterized by widely variable cutaneous Staphylococcus aureus abundance that contributes to disease severity and rapidly responds to type 2 immune blockade (i.e., dupilumab). The molecular mechanisms regulating S. aureus levels between AD subjects remain poorly understood.To investigate host genes that may be predictive of S. aureus abundance and correspond with AD severity.Data derived from the NIH/NIAID-funded (NCT03389893 [ADRN-09]) randomized, double-blind, and placebo-controlled multicenter study of dupilumab in adults (n=71 subjects) with moderate-severe AD. Bulk RNA-sequencing of skin biopsies (n=57 lesional, 55 non-lesional) was compared to epidermal S. aureus abundance, lipidomics, and AD clinical measures.S. aureus abundance and ceramide synthase 1 (CERS1) expression positively correlated at baseline across both non-lesional (r=0.29, p=0.030) and lesional (r=0.41, p=0.0015) skin. Lesional CERS1 expression also positively correlated with AD severity (i.e., SCORing AD [SCORAD] r=0.44, p=0.0006) and skin barrier dysfunction (transepidermal water loss area under the curve [TEWL AUC] r=0.31, p=0.025) at baseline. CERS1 expression (forms C18:0-sphingolipids) was negatively associated with elongation of very long chain fatty acids (ELOVL6; C16:0?C18:0) expression and corresponded with a shorter chain length sphingolipid composition. Dupilumab rapidly reduced CERS1 expression (day 7) and ablated the relationship with S. aureus abundance and ELOVL6 expression by day 21.CERS1 is a unique molecular biomarker of S. aureus abundance and AD severity that may contribute to dysfunctional skin barrier and shorter chain sphingolipid composition through fatty acid sequestration as a maladaptive compensatory response to reduced ELOVL6.

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