Interplay of Staphylococcal and Host Proteases Promotes Skin Barrier Disruption in Netherton Syndrome
Michael R. Williams,
Laura Cau,
Yichen Wang,
Drishti Kaul,
James A. Sanford,
Livia S. Zaramela,
Shadi Khalil,
Anna M. Butcher,
Karsten Zengler,
Alexander R. Horswill,
Christopher L. Dupont,
Alain Hovnanian,
Richard L. Gallo
Affiliations
Michael R. Williams
Department of Dermatology, University of California, San Diego, San Diego, CA 92093, USA; Corresponding author
Laura Cau
Department of Dermatology, University of California, San Diego, San Diego, CA 92093, USA; SILAB, R&D Department, Brive, France; Corresponding author
Yichen Wang
INSERM, UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute and Université Paris Descartes-Sorbonne Paris Cité, Paris, France
Drishti Kaul
J. Craig Venter Institute, La Jolla, CA 92093, USA
James A. Sanford
Department of Dermatology, University of California, San Diego, San Diego, CA 92093, USA
Livia S. Zaramela
Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA
Shadi Khalil
Department of Dermatology, University of California, San Diego, San Diego, CA 92093, USA; University of Virginia School of Medicine, Charlottesville, VA 22908, USA
Anna M. Butcher
Department of Dermatology, University of California, San Diego, San Diego, CA 92093, USA
Karsten Zengler
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
Alexander R. Horswill
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
Christopher L. Dupont
J. Craig Venter Institute, La Jolla, CA 92093, USA
Alain Hovnanian
INSERM, UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute and Université Paris Descartes-Sorbonne Paris Cité, Paris, France
Richard L. Gallo
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; Corresponding author
Summary: 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. : Williams et al. show how an abnormal skin microbiome promotes inflammation associated with Netherton syndrome, a monogenic disorder in the human protease inhibitor SPINK5. Subjects with Netherton syndrome have excess colonization by S. aureus or S. epidermidis that then produce and promote increased protease production in the epidermis. Keywords: Netherton syndrome, S. aureus, S. epidermidis, proteases, epidermal barrier, skin inflammation, skin microbiome
