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Cell Rep. 2020 Mar 3;30(9):2923-2933.e7. doi: 10.1016/j.celrep.2020.02.021.

Interplay of Staphylococcal and Host Proteases Promotes Skin Barrier Disruption in Netherton Syndrome.

Author information

1
Department of Dermatology, University of California, San Diego, San Diego, CA 92093, USA. Electronic address: mrw006@ucsd.edu.
2
Department of Dermatology, University of California, San Diego, San Diego, CA 92093, USA; SILAB, R&D Department, Brive, France. Electronic address: lauracaufacy@gmail.com.
3
INSERM, UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute and Université Paris Descartes-Sorbonne Paris Cité, Paris, France.
4
J. Craig Venter Institute, La Jolla, CA 92093, USA.
5
Department of Dermatology, University of California, San Diego, San Diego, CA 92093, USA.
6
Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA.
7
Department of Dermatology, University of California, San Diego, San Diego, CA 92093, USA; University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
8
Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Center for Microbiome Innovation, University of California, San Diego, San Diego, CA 92093, USA; Department of Bioengineering, University of California, San Diego, CA 92093, USA.
9
Department of Veterans Affairs Denver Health Care System, Denver, CO, USA; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora 80045, CO, USA.
10
Department of Dermatology, University of California, San Diego, San Diego, CA 92093, USA; Center for Microbiome Innovation, University of California, San Diego, San Diego, CA 92093, USA. Electronic address: rgallo@ucsd.edu.

Abstract

Netherton syndrome (NS) is a monogenic skin disease resulting from loss of function of lymphoepithelial Kazal-type-related protease inhibitor (LEKTI-1). In this study we examine if bacteria residing on the skin are influenced by the loss of LEKTI-1 and if interaction between this human gene and resident bacteria contributes to skin disease. Shotgun sequencing of the skin microbiome demonstrates that lesional skin of NS subjects is dominated by Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis). Isolates of either species from NS subjects are able to induce skin inflammation and barrier damage on mice. These microbes promote skin inflammation in the setting of LEKTI-1 deficiency due to excess proteolytic activity promoted by S. aureus phenol-soluble modulin α as well as increased bacterial proteases staphopain A and B from S. aureus or EcpA from S. epidermidis. These findings demonstrate the critical need for maintaining homeostasis of host and microbial proteases to prevent a human skin disease.

KEYWORDS:

Netherton syndrome; S. aureus; S. epidermidis; epidermal barrier; proteases; skin inflammation; skin microbiome

PMID:
32130897
DOI:
10.1016/j.celrep.2020.02.021
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Conflict of interest statement

Declaration of Interests R.L.G. is a co-founder, scientific advisor, consultant, and has equity in MatriSys Biosciences and is a consultant, receives income, and has equity in Sente. All other authors declare no competing interests.

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