Dataset Information

The human pathobiont Malassezia furfur secreted protease MfSAP1 regulates cell dispersal and exacerbates skin inflammation

ABSTRACT: Malassezia forms the dominant eukaryotic microbial community on the human skin. The Malassezia genus possesses a repertoire of secretory hydrolytic enzymes involved in protein and lipid metabolism which alter the external cutaneous environment. The exact role of most Malassezia secreted enzymes, including those in interaction with the epithelial surface, are not well characterized. In this study, we compared the expression level of secreted proteases, lipases, phospholipases, and sphingomyelinases of Malassezia globosa in healthy subjects and seborrheic dermatitis or atopic dermatitis patients. We observed upregulated gene expression of the previously characterized secretory aspartyl protease MgSAP1 in both the lesional and non-lesional skin sites of affected compared to healthy subjects. To explore the functional roles of MgSAP1 in skin disease, we generated a knockout mutant of the homologous protease MfSAP1 in the genetically tractable Malassezia furfur. We observed the loss of MfSAP1 resulted in dramatic changes in the cell adhesion and dispersal in both culture and a human 3D reconstituted epidermis model. In a murine model of Malassezia colonization, we further demonstrated MfSAP1 contributes to inflammation as observed by reduced edema and myeloid pustule formation with the knockout mutant versus wildtype. Taken together, we show that this dominant secretory Malassezia aspartyl protease has an important role in enabling a planktonic cellular state that can potentially aid in colonization and additionally as a virulence factor in barrier-compromised skin, further highlighting the importance of considering the contextual relevance when evaluating the functions of secreted microbial enzymes.

ORGANISM(S): Cellular Organisms

SUBMITTER: Hao Li and Thomas L. Dawson

PROVIDER: PXD033336 | JPOST Repository | Fri Nov 11 00:00:00 GMT 2022

REPOSITORIES: jPOST

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Dataset's files

Source:

			Action	DRS
	20191204_KT_JG_band3.pdResult	Other
	20191204_KT_JG_band3_Proteins.txt	Txt
	20191204_KT_JG_band4.pdResult	Other
	20191204_KT_JG_band4_Proteins.txt	Txt
	20191212_KT_JG_band1.pdResult	Other

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Publications

The human pathobiont Malassezia furfur secreted protease Mfsap1 regulates cell dispersal and exacerbates skin inflammation.

Goh Joleen P Z JPZ Ruchti Fiorella F Poh Si En SE Koh Winston L C WLC Tan Kiat Yi KY Lim Yan Ting YT Thng Steven T G STG Sobota Radoslaw M RM Hoon Shawn S SS Liu Chenxi C O'Donoghue Anthony J AJ LeibundGut-Landmann Salomé S Oon Hazel H HH Li Hao H Dawson Thomas L TL

Proceedings of the National Academy of Sciences of the United States of America 20221129 49

Malassezia form the dominant eukaryotic microbial community on the human skin. The Malassezia genus possesses a repertoire of secretory hydrolytic enzymes involved in protein and lipid metabolism which alter the external cutaneous environment. The exact role of most Malassezia secreted enzymes, including those in interaction with the epithelial surface, is not well characterized. In this study, we compared the expression level of secreted proteases, lipases, phospholipases, ...[more]

PMID: 36442106

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Project description:Background: Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease with skin barrier defects and a misdirected type 2 immune response against harmless antigens. The skin microbiome in AD is characterized by a reduction in microbial diversity with a dominance of staphylococci, including Staphylococcus epidermidis (S. epidermidis). Objective: To assess whether S. epidermidis antigens play a role in AD, we screened for candidate allergens and studied the T-cell and humoral immune response against the extracellular serine protease (Esp). Methods: To identify candidate allergens, we analyzed the binding of human serum IgG4, as a surrogate of IgE, to S. epidermidis extracellular proteins using 2-dimensional immunoblotting and mass spectrometry. We then measured serum IgE and IgG1 binding to recombinant Esp by ELISA in healthy and AD individuals. We also stimulated T-cells from AD patients and control subjects with Esp and measured the secreted cytokines. Finally, we analyzed the proteolytic activity of Esp against IL-33 and determined the cleavage sites by mass spectrometry. Results: We identified Esp as the dominant candidate allergen of S. epidermidis. Esp-specific IgE was present in human serum; AD patients had higher concentrations than controls. T-cells reacting to Esp were detectable in both AD patients and healthy controls. The T-cell response in healthy adults was characterized by IL-17, IL-22, IFN-gamma, and IL-10, whereas the AD patients' T-cells lacked IL-17 production and released only low amounts of IL-22, IFN-gamma, and IL-10. In contrast, Th2 cytokine release was higher in T-cells from AD patients than from healthy controls. Mature Esp cleaved and activated the alarmin IL-33. Conclusions: The extracellular serine protease Esp of S. epidermidis can activate IL-33. As an antigen, Esp elicits a type 2-biased antibody and T-cell response in AD patients. This suggests that S. epidermidis can aggravate AD through the allergenic properties of Esp.

Dataset Information

The human pathobiont Malassezia furfur secreted protease MfSAP1 regulates cell dispersal and exacerbates skin inflammation

Dataset's files

Publications

The human pathobiont <i>Malassezia furfur</i> secreted protease Mfsap1 regulates cell dispersal and exacerbates skin inflammation.

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