CERS1 is a biomarker of Staphylococcus aureus abundance and atopic dermatitis severity - 17/10/24

Doi : 10.1016/j.jaci.2024.09.017

H. Mark Kenney, MD, PhD ^a, Takeshi Yoshida, PhD ^b, Evgeny Berdyshev, PhD ^c, Agustin Calatroni, MS ^d, Steven R. Gill, PhD ^e, Eric L. Simpson, MD ^f, Stephanie Lussier, MS ^d, Mark Boguniewicz, MD ^g, Tissa Hata, MD ^h, Zelma C. Chiesa Fuxench, MD, MSCE ⁱ, Anna De Benedetto, MD ^b, Peck Y. Ong, MD ^j, Justin Ko, MD ^k, Wendy Davidson, PhD ^l, Gloria David, PhD ^d, Patrick M. Schlievert, PhD ^m, Donald Y.M. Leung, MD, PhD ^g, Lisa A. Beck, MD ^a,^b,^⁎
^a Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
^b Department of Dermatology, University of Rochester Medical Center, Rochester, NY
^c Department of Medicine, National Jewish Health and University of Colorado School of Medicine, Denver, Colo
^d Rho Inc, Durham, NC
^e Department of Microbiology & Immunology, University of Rochester Medical Center, Rochester, NY
^f Department of Dermatology, Oregon Health and Science University, Portland, Ore
^g Division of Allergy-Immunology, Department of Pediatrics, National Jewish Health and University of Colorado School of Medicine, Denver, Colo
^h Department of Dermatology, University of California, San Diego, Calif
ⁱ Department of Dermatology, University of Pennsylvania, Philadelphia, Pa
^j Department of Pediatrics, University of Southern California, Division of Clinical Immunology and Allergy Children’s Hospital Los Angeles, Los Angeles, Calif
^k Department of Dermatology, Stanford University, Stanford, Calif
^l Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
^m Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa

^∗Corresponding author: Lisa A. Beck, MD, 601 Elmwood Ave, Box 697, Rochester NY 14642.601 Elmwood AveBox 697RochesterNY14642

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Thursday 17 October 2024

Abstract

Background

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 (ie, dupilumab). The molecular mechanisms regulating S aureus levels between AD subjects remain poorly understood.

Objective

We investigated host genes that may be predictive of S aureus abundance and correspond with AD severity.

Methods

We studied data derived from the National Institutes of Health/National Institute of Allergy and Infectious Diseases–funded (NCT03389893 [ADRN-09]) randomized, double-blind, placebo-controlled multicenter study of dupilumab in adults (n = 71 subjects) with moderate-to-severe AD. Bulk RNA sequencing of skin biopsy samples (n = 57 lesional, 55 nonlesional) was compared to epidermal S aureus abundance, lipidomic, and AD clinical measures.

Results

S aureus abundance and ceramide synthase 1 (CERS1) expression positively correlated at baseline across both nonlesional (r = 0.29, P = .030) and lesional (r = 0.41, P = .0015) skin. Lesional CERS1 expression also positively correlated with AD severity (ie, SCORAD r = 0.44, P = .0006) and skin barrier dysfunction (transepidermal water loss area under the curve r = 0.31, P = .025) at baseline. CERS1 expression (forms C_18:0 sphingolipids) was negatively associated with elongation of very long-chain fatty acids (ELOVL6; C_16:0→C_18:0) 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.

Conclusion

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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Key words : Atopic dermatitis, type 2 immunity, transcriptomics, microbiome, Staphylococcus aureus, dupilumab, skin barrier, sphingolipids, ceramide synthase, CERS1

Abbreviations used : AD, AUC, Cer, CERS, CFA, CFU, DEG, DHCer, EASI, ELOVL, MLR, NRS, rCFU, SCORAD, SM, TEWL

Plan

Methods

Human subjects data collection

Additional methods

Results

CERS1 expression is positively associated with S aureus abundance at both nonlesional and lesional sites

AD severity and barrier dysfunction positively correlate with CERS1 expression at lesional sites

CERS1 expression rapidly declines with dupilumab treatment in AD

CERS1 exhibits ELOVL6 dependence during active inflammation

CERS1 expression is potentially related to shorter-CFA sphingolipid skew in AD

Discussion

Portions of the transcriptomics data (days 0-7), along with measures of Staphylococcus aureus abundance, skin barrier dysfunction (ie, transepidermal water loss), and atopic dermatitis clinical severity/symptoms have been published previously: Simpson EL, Schlievert PM, Yoshida T, Lussier S, Boguniewicz M, Hata T, et al, “Rapid reduction in Staphylococcus aureus in atopic dermatitis subjects following dupilumab treatment,” J Allergy Clin Immunol 2023;152:1179-95, https://doi.org/10.1016/j.jaci.2023.05.026. The authors of this prior work retain the right to prepare other derivative works or to reuse portions in other works, given full acknowledgment of the original publication. Our current data utilization has been reconceptualized and reutilized for the unique purposes of the study objectives.