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The Skin Commensal Yeast Malassezia globosa Thwarts Bacterial Biofilms to Benefit the Host

  • Giuseppe Ianiri
    Affiliations
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA
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  • Joseph Heitman
    Affiliations
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA
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  • Annika Scheynius
    Correspondence
    Correspondence: Annika Scheynius, Department of Clinical Science and Education, Karolinska Institutet, and Sachs' Children and Youth Hospital, Södersjukhuset, SE-118 83 Stockholm, Sweden.
    Affiliations
    Science for Life Laboratory, Department of Clinical Science and Education, Karolinska Institutet, and Sachs' Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden
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      Malassezia are abundant, lipid-dependent, commensal yeasts in the skin microbiome that also have a pathogenic lifestyle associated with several common skin disorders. Malassezia genomes encode myriad lipases and proteases thought to mediate lipid utilization and pathogenesis. Li et al. report the biochemical characterization of a unique secreted aspartyl protease produced by Malassezia globosa, MgSAP1, and demonstrate its active role in hindering biofilm formation of the bacterium Staphylococcus aureus. Because biofilms are an established virulence attribute of S. aureus, this study reveals a potential benefit to the host of the fungal aspartyl protease MgSAP1 and opens the door for the investigation of the roles of such molecules in microbial interactions and their possible effects on the host.
      A secreted aspartyl protease from Malassezia globosa exhibits unexpected hydrolytic activity that acts on Staphylococcus aureus biofilms.

      Fungi of the genus Malassezia

      The skin of humans and animals is colonized by numerous microorganisms that constitute the skin microbiome. These include commensal bacteria and fungi that establish a nonpathogenic interaction with the host, but in certain circumstances, such as immune conditions within the host, or intrinsic microbial imbalance, some commensals can become pathogenic or beneficial. The study by
      • Li H.
      • Goh B.N.
      • Teh W.K.
      • Jiang Z.
      • Goh J.P.Z.
      • Goh A.
      • et al.
      Skin commensal Malassezia globosa secreted protease attenuates Staphylococcus aureus biofilm formation.
      reports a previously unknown beneficial role for a secreted aspartyl protease produced by the fungus Malassezia globosa.
      Malassezia species are the most abundant fungal skin inhabitant of humans (
      • Findley K.
      • Oh J.
      • Yang J.
      • Conlan S.
      • Deming C.
      • Meyer J.A.
      • et al.
      Topographic diversity of fungal and bacterial communities in human skin.
      ). This genus includes a monophyletic group of yeasts within the basidiomycetes that is closely related to the smut plant pathogen Ustilago maydis and more distantly related to skin-infecting fungal species, such as Candida albicans and the dermatophytes. The unique Malassezia genus currently includes 17 species, of which M. globosa, M. restricta, and M. sympodialis are most commonly associated with humans (
      • Sparber F.
      • LeibundGut-Landmann S.
      Host responses to Malassezia spp. in the mammalian skin.
      ). A common feature is the inability of Malassezia to synthesize lipids due to the loss of the fatty acid synthase gene, and as a consequence, these species mainly colonize sebaceous skin. Comprehensive molecular and genetic research on Malassezia has highlighted unique features compared with other fungi, such as a reduction in genome size (as small as approximately 7–9 Mbp) with extensive loss of genes encoding hydrolases and other enzymes involved in carbohydrate metabolism, and concomitant expansion of genes encoding secreted lipases and proteases thought to mediate lipid utilization and play roles in pathogenesis (
      • Wu G.
      • Zhao H.
      • Li C.
      • Rajapakse M.P.
      • Wong W.C.
      • Xu J.
      • et al.
      Genus-wide comparative genomics of Malassezia delineates its phylogeny, physiology, and niche adaptation on human skin.
      ).

      Is Malassezia a beneficial skin inhabitant?

      Although Malassezia are commensal inhabitants of the skin, they are associated with several skin disorders, including pityriasis versicolor, dandruff, seborrheic dermatitis, atopic dermatitis (AD), and folliculitis (
      • Saunders C.W.
      • Scheynius A.
      • Heitman J.
      Malassezia fungi are specialized to live on skin and associated with dandruff, eczema, and other skin diseases.
      ). It is presumed that Malassezia strains associated with these clinical conditions are derived from normal commensal strains, but this has not been experimentally proven. As a result, the pathophysiology of Malassezia and the mechanisms that govern its shift from commensal to pathogen are poorly understood.
      It is reasonable to hypothesize that the immune system has adapted to the commensal nature of Malassezia and thus tolerates its presence on the skin, but the immune system can also recognize the fungus as a pathogen and respond. Malassezia can be recognized by the host, either directly through membrane-bound pattern recognition receptors or indirectly through production of inflammatory metabolites released by hydrolysis of sebum by fungal lipases and proteases. These metabolites are thought to be responsible for clinical dandruff and seborrheic dermatitis (
      • White T.C.
      • Findley K.
      • Dawson Jr., T.L.
      • Scheynius A.
      • Boekhout T.
      • Cuomo C.A.
      • et al.
      Fungi on the skin: dermatophytes and Malassezia.
      ).
      Another way in which Malassezia is known to interact with the immune system is through the production of specific allergens. These include a set of nine conserved and four unknown proteins identified in the M. sympodialis genome (
      • Gioti A.
      • Nystedt B.
      • Li W.
      • Xu J.
      • Andersson A.
      • Averette A.F.
      • et al.
      Genomic insights into the atopic eczema-associated skin commensal yeast Malassezia sympodialis.
      ). Approximately half of adult patients with AD have allergen-specific IgE and T-cell reactivity to Malassezia, which are rarely observed in respiratory allergies, suggesting a host-microbe interaction related to the skin environment in AD (
      • White T.C.
      • Findley K.
      • Dawson Jr., T.L.
      • Scheynius A.
      • Boekhout T.
      • Cuomo C.A.
      • et al.
      Fungi on the skin: dermatophytes and Malassezia.
      ). A clinical hallmark of AD is dry, itchy skin with increased permeability and water loss. There is a distinct reciprocal expression pattern of induced inflammatory genes and repressed lipid metabolism genes (
      • Sääf A.M.
      • Tengvall-Linder M.
      • Chang H.Y.
      • Adler A.S.
      • Wahlgren C.-F.
      • Scheynius A.
      • et al.
      Global expression profiling in atopic eczema reveals reciprocal expression of inflammatory and lipid genes.
      ). This results in an inhospitable environment for the lipid-dependent Malassezia, and there is an increased pH level on AD skin that stimulates the yeast to release more allergens compared with culture at normal skin pH (
      • Selander C.
      • Zargari A.
      • Mollby R.
      • Rasool O.
      • Scheynius A.
      Higher pH level, corresponding to that on the skin of patients with atopic eczema, stimulates the release of Malassezia sympodialis allergens.
      ).
      Yet another way for Malassezia to communicate with the host is through the release of extracellular nanosized vesicles, designated MalaEx, that carry allergens and can induce inflammatory cytokine responses (
      • Gehrmann U.
      • Qazi K.R.
      • Johansson C.
      • Hultenby K.
      • Karlsson M.
      • Lundeberg L.
      • et al.
      Nanovesicles from Malassezia sympodialis and host exosomes induce cytokine responses—novel mechanisms for host-microbe interactions in atopic eczema.
      ). MalaEx, which contain small RNAs as a cargo (
      • Rayner S.
      • Bruhn S.
      • Vallhov H.
      • Andersson A.
      • Billmyre R.B.
      • Scheynius A.
      Identification of small RNAs in extracellular vesicles from the commensal yeast Malassezia sympodialis.
      ), have the potential—like other fungal extracellular vesicles—to deliver functional mRNAs and microRNA-like RNAs to recipient host cells, thereby interfering with the host RNAi machinery to silence host immune genes and cause infection (
      • Weiberg A.
      • Wang M.
      • Lin F.M.
      • Zhao H.
      • Zhang Z.
      • Kaloshian I.
      • et al.
      Fungal small RNAs suppress plant immunity by hijacking host RNA interference pathways.
      ).
      Although establishing the basis and the relationship between commensalism and pathogenicity is a recognized and active research field, Malassezia interactions with other microbes on the skin and their effects on the host are largely unexplored.
      • Li H.
      • Goh B.N.
      • Teh W.K.
      • Jiang Z.
      • Goh J.P.Z.
      • Goh A.
      • et al.
      Skin commensal Malassezia globosa secreted protease attenuates Staphylococcus aureus biofilm formation.
      reported that a secreted aspartyl protease produced by M. globosa displays antibiofilm properties against Staphylococcus aureus, which is responsible for skin and soft tissue infections and which is frequently associated with skin infections in AD. Previous genomic studies revealed a robust secretory repertoire for all species belonging to the genus Malassezia, consistent with the importance of these hydrolytic enzymes for Malassezia biology and pathophysiology (
      • Wu G.
      • Zhao H.
      • Li C.
      • Rajapakse M.P.
      • Wong W.C.
      • Xu J.
      • et al.
      Genus-wide comparative genomics of Malassezia delineates its phylogeny, physiology, and niche adaptation on human skin.
      ,
      • Zhu Y.
      • Engstrom P.G.
      • Tellgren-Roth C.
      • Baudo C.D.
      • Kennell J.C.
      • Sun S.
      • et al.
      Proteogenomics produces comprehensive and highly accurate protein-coding gene annotation in a complete genome assembly of Malassezia sympodialis.
      ).
      RNAseq analysis revealed that 2 of the 15 predicted aspartyl proteases of M. globosa, encoded by MGL_3328 and MGL_1932, were highly expressed in vitro during growth in both rich and minimal media. Through biochemical analyses,
      • Li H.
      • Goh B.N.
      • Teh W.K.
      • Jiang Z.
      • Goh J.P.Z.
      • Goh A.
      • et al.
      Skin commensal Malassezia globosa secreted protease attenuates Staphylococcus aureus biofilm formation.
      characterized a specific aspartyl protease activity, revealing strong cleavage of specific substrates (RPKPYAvWM and RPKPVEvWR), increasing activity in the first 16 hours of growth, and a pH optimum between 4 and 5. Mass spectrometry and trypsin in-gel digest analyses identified MGL_1932 as the major aspartyl protease in culture, and it was named MgSAP1 (from M. globosa secreted aspartyl protease 1). Further analyses demonstrated that MgSAP1 has a cleavage preference adjacent to aromatic residues, in particular tryptophan, which distinguishes it from other known proteases.
      Li et al. then aimed to establish if the secreted protease MgSAP1 was (1) produced in situ on human skin, (2) had any role in Malassezia biology and/or pathophysiology, and (3) could potentially mediate interactions with existing skin microflora. MgSAP1 was found to be expressed on the faces of 17 of 18 healthy male and female volunteers, indicating its ubiquitous production. Among the skin microflora, S. aureus coexists in many sites with M. globosa (
      • Oh J.
      • Byrd A.L.
      • Deming C.
      • Conlan S.
      • Kong H.H.
      • Segre J.A.
      Biogeography and individuality shape function in the human skin metagenome.
      ) and produces protein A (SpA), which is essential for biofilm formation, a major S. aureus virulence factor (
      • Archer N.K.
      • Mazaitis M.J.
      • Costerton J.W.
      • Leid J.G.
      • Powers M.E.
      • Shirtliff M.E.
      Staphylococcus aureus biofilms: properties, regulation and roles in human disease.
      ). Because SpA is rich in lysine and aromatic residues, the authors hypothesized that it could be hydrolyzed by MgSAP1, thus impacting S. aureus pathogenicity. Strikingly, MgSPA1 rapidly degraded recombinant SpA in vitro and strongly reduced the in situ volume of S. aureus biofilm formation without affecting bacterial viability. A representation of MgSAP1-mediated biofilm destruction is shown in Figure 1.
      Figure 1
      Figure 1Staphylococcus aureus biofilms are inhibited by an aspartyl protease secreted by Malassezia globosa. On the left, a schematic view illustrates a biofilm formed on the skin by the bacterium S. aureus and the inflammation that is produced as a host response. On the right, formation of the biofilm is inhibited by the secreted aspartyl protease MgSAP1 of M. globosa, and as a consequence, there is predicted to be reduced inflammation of the skin.
      This study raises questions about the specific roles of Malassezia proteases, as their common in situ expression has been correlated with their involvement in pathogenesis (
      • White T.C.
      • Findley K.
      • Dawson Jr., T.L.
      • Scheynius A.
      • Boekhout T.
      • Cuomo C.A.
      • et al.
      Fungi on the skin: dermatophytes and Malassezia.
      ). This predicted function as virulence factors is likely based on the role of analogous proteases in more well-studied fungi that can live on the skin such as the dermatophytes and C. albicans. In fact, their genome comparisons reveal a significant expansion of genes predicted to encode proteases in Malassezia, dermatophytes, and C. albicans, suggesting an important role of proteases in evolution and adaptation on the skin. In C. albicans, secreted aspartyl proteases have long been recognized as virulence factors that act by promoting adhesion to, invasion of, and damage to epithelial cells and tissues and by inducing the secretion of proinflammatory cytokines independently from their proteolytic activity (
      • Pietrella D.
      • Rachini A.
      • Pandey N.
      • Schild L.
      • Netea M.
      • Bistoni F.
      • et al.
      The inflammatory response induced by aspartic proteases of Candida albicans is independent of proteolytic activity.
      ). With respect to dermatophytes, these fungi secrete an abundance of proteases for multiple functions, such as adherence on the skin, keratin digestion for penetration, and modulation of cell metabolism and the host immune system (
      • de Hoog S.
      • Monod M.
      • Dawson T.
      • Boekhout T.
      • Mayser P.
      • Gräser Y.
      Skin fungi from colonization to infection.
      ,
      • White T.C.
      • Findley K.
      • Dawson Jr., T.L.
      • Scheynius A.
      • Boekhout T.
      • Cuomo C.A.
      • et al.
      Fungi on the skin: dermatophytes and Malassezia.
      ).
      The study by
      • Li H.
      • Goh B.N.
      • Teh W.K.
      • Jiang Z.
      • Goh J.P.Z.
      • Goh A.
      • et al.
      Skin commensal Malassezia globosa secreted protease attenuates Staphylococcus aureus biofilm formation.
      represents a paradigmatic example of a fungal-bacterial interaction that is mediated by a secreted molecule and that potentially results in a beneficial effect for the host. Fungal and bacterial interactions are common, although they are understudied and technically challenging to elucidate. However, there is an increasing awareness of their biological and pathophysiological importance (
      • Peleg A.Y.
      • Hogan D.A.
      • Mylonakis E.
      Medically important bacterial-fungal interactions.
      ). As an example,
      • Graham C.E.
      • Cruz M.R.
      • Garsin D.A.
      • Lorenz M.C.
      Enterococcus faecalis bacteriocin EntV inhibits hyphal morphogenesis, biofilm formation, and virulence of Candida albicans.
      recently described an interesting interaction between the bacterium Enterococcus faecalis and C. albicans. These two microbes occupy overlapping niches in the mammalian microbiome and display antagonistic activity resulting in reduced virulence for both microbes. In C. albicans, this reduced virulence was attributed to the reduction of hyphal development and biofilm formation due to the activity of the secreted E. faecalis bacteriocin, EntV (
      • Graham C.E.
      • Cruz M.R.
      • Garsin D.A.
      • Lorenz M.C.
      Enterococcus faecalis bacteriocin EntV inhibits hyphal morphogenesis, biofilm formation, and virulence of Candida albicans.
      ).

      Conclusions

      The study of
      • Li H.
      • Goh B.N.
      • Teh W.K.
      • Jiang Z.
      • Goh J.P.Z.
      • Goh A.
      • et al.
      Skin commensal Malassezia globosa secreted protease attenuates Staphylococcus aureus biofilm formation.
      reveals that the commensal and sometimes pathogenic fungus M. globosa produces an aspartyl protease, unique in its evolutionary trajectory and substrate specificity, which impacts a recognized virulence attribute of a commensal and pathogenic bacteria, thus potentially resulting in unexpected benefits for the host. This finding underscores the importance of in vivo studies to determine the function of unknown proteins during microbial interactions, and the beneficial or detrimental impact that they might have on the host. For example, whether the characterized MgSAP1 protease also plays a role in Malassezia pathogenesis as described for other aspartyl proteases is still unknown. There is a crucial need to develop and establish reliable host-pathogen models to study how Malassezia interacts with both cells in the skin and different immune cells, and with other microbes that live on the skin, as well as the induced immune responses in robust mouse and humanized-mouse models of infection. This coupled with the recent development of tools for targeted and insertional mutagenesis (
      • Celis A.M.
      • Vos A.M.
      • Triana S.
      • Medina C.A.
      • Escobar N.
      • Restrepo S.
      • et al.
      Highly efficient transformation system for Malassezia furfur and Malassezia pachydermatis using Agrobacterium tumefaciens-mediated transformation.
      ,
      • Ianiri G.
      • Averette A.F.
      • Kingsbury J.M.
      • Heitman J.
      • Idnurm A.
      Gene function analysis in the ubiquitous human commensal and pathogen Malassezia genus.
      ) will help to characterize the mechanisms that establish the commensal, pathogenic, and beneficial lifestyles of Malassezia species on the skin.

      Conflict of Interest

      AS has co-authored large collaborative publications with the senior author (Tom Dawson) of the present article commented on herein, published in 2013 (
      • Gioti A.
      • Nystedt B.
      • Li W.
      • Xu J.
      • Andersson A.
      • Averette A.F.
      • et al.
      Genomic insights into the atopic eczema-associated skin commensal yeast Malassezia sympodialis.
      ), 2014 (
      • White T.C.
      • Findley K.
      • Dawson Jr., T.L.
      • Scheynius A.
      • Boekhout T.
      • Cuomo C.A.
      • et al.
      Fungi on the skin: dermatophytes and Malassezia.
      ), 2015 (
      • Wu G.
      • Zhao H.
      • Li C.
      • Rajapakse M.P.
      • Wong W.C.
      • Xu J.
      • et al.
      Genus-wide comparative genomics of Malassezia delineates its phylogeny, physiology, and niche adaptation on human skin.
      ), and 2017 (
      • Zhu Y.
      • Engstrom P.G.
      • Tellgren-Roth C.
      • Baudo C.D.
      • Kennell J.C.
      • Sun S.
      • et al.
      Proteogenomics produces comprehensive and highly accurate protein-coding gene annotation in a complete genome assembly of Malassezia sympodialis.
      ). This did not influence the views presented here with respect to the Commentary published in the Journal of Investigative Dermatology. JH has co-authored large collaborative publications with the senior author (Tom Dawson) of the article discussed, published in 2013 (
      • Gioti A.
      • Nystedt B.
      • Li W.
      • Xu J.
      • Andersson A.
      • Averette A.F.
      • et al.
      Genomic insights into the atopic eczema-associated skin commensal yeast Malassezia sympodialis.
      ), 2015 (
      • Wu G.
      • Zhao H.
      • Li C.
      • Rajapakse M.P.
      • Wong W.C.
      • Xu J.
      • et al.
      Genus-wide comparative genomics of Malassezia delineates its phylogeny, physiology, and niche adaptation on human skin.
      ), and 2017 (
      • Zhu Y.
      • Engstrom P.G.
      • Tellgren-Roth C.
      • Baudo C.D.
      • Kennell J.C.
      • Sun S.
      • et al.
      Proteogenomics produces comprehensive and highly accurate protein-coding gene annotation in a complete genome assembly of Malassezia sympodialis.
      ). This did not influence the views presented here with respect to the article published in the Journal of Investigative Dermatology. AS has research support from the Swedish Research Council Medicine, the Cancer and Allergy Foundation, the ChAMP (Centre for Allergy Research Highlights Asthma Markers of Phenotype) consortium that is funded by the Swedish Foundation for Strategic Research, the Karolinska Institutet, AstraZeneca and Science for Life Laboratory Joint Research Collaboration. AS is a member in the Joint Steering Committee for the Human Translational Microbiome Program at SciLifeLab/Karolinska Institutet together with Ferring Pharmaceuticals, Switzerland, during 2016–2018, outside the scope of this work and without any financial support. GI states no conflict of interest.

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      Linked Article

      • Skin Commensal Malassezia globosa Secreted Protease Attenuates Staphylococcus aureus Biofilm Formation
        Journal of Investigative DermatologyVol. 138Issue 5
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          Skin provides the first defense against pathogenic micro-organisms and is also colonized by a diverse microbiota. Phylogenetic analysis of whole skin microbiome at different skin sites in health and disease has generated important insights on possible microbial involvement in modulating skin health. However, functional roles of the skin microbial community remain unclear. The most common sebaceous skin commensal yeasts are the basidiomycetes, Malassezia. Here, we characterized the dominant secreted Malassezia globosa protease in culture and subsequently named it Malassezia globosa Secreted Aspartyl Protease 1 (MgSAP1).
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