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Malassezia globosa and restricta: Breakthrough Understanding of the Etiology and Treatment of Dandruff and Seborrheic Dermatitis through Whole-Genome Analysis

      Dandruff and seborrheic dermatitis (D/SD) share an etiology dependent upon three factors: sebum, microbial metabolism (specifically, Malassezia yeasts), and individual susceptibility. Advances in microbiological and analytical techniques permit a more detailed understanding of these etiologic factors, especially the role of Malassezia. Malassezia are lipid-dependent and demonstrate adaptation allowing them to exploit a narrow niche on sebum-rich skin. Work in our and our collaborators' laboratories has focused on understanding these adaptations by detailed analysis of biochemistry and gene expression. We have shown that Malassezia globosa and M. restricta predominate on dandruff scalp, that oleic acid alone can initiate dandruff-like desquamation, that M. globosa is the most likely initiating organism by virtue of its high lipase activity, and that an M. globosa lipase is expressed on human scalp. Considering the importance of M. globosa in D/SD (and the overall importance of commensal fungi), we have sequenced the M. globosa and M. restricta genomes. Genomic analysis indicates key adaptations to the skin environment, several of which yield important clues to the role Malassezia play in human disease. This work offers the promise of defining new treatments to D/SD that are targeted at changing the level or activities of Malassezia genes.
      D/SD
      dandruff and seborrheic dermatitis

      Introduction

      Dandruff and seborrheic dermatitis (D/SD) are common abnormal skin conditions characterized by flaking and itch. In dandruff, the flakes are loosely adherent, oily, generally not associated with overt inflammation, and restricted to the scalp. In seborrheic dermatitis, the flakes are greasy and yellowish, and inflammation is observed. In SD, the most common affected sites are the scalp, nasolabial folds, ears, eyebrows, and chest. Although the conditions differ in some respects, they appear to represent a continuum of symptoms with a common etiology (
      • Pierard Franchimont C.J.
      • Hermanns J.F.
      • Degreef H.
      • Pierard G.E.
      From axioms to new insights into dandruff.
      ;
      • Gupta A.K.
      • Bluhm R.
      • Cooper E.A.
      • Summerbarr R.Z.
      • Batra R.
      Seborrheic dermatitis.
      ). More than 50% of adults may be affected by these conditions and their socioeconomic impact is very high. For seborrheic dermatitis alone, the health care direct, indirect, and intangible costs exceeded $1.4 billon in the United States in 2004 (
      • Bickers D.R.
      • Lim H.W.
      • Margolis D.
      • Weinstock M.A.
      • Goodman C.
      • Falkner E.
      • et al.
      The burden of skin diseases: 2004, a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology.
      ). Despite the impact of these conditions, their etiology is poorly understood.
      It is clear that D/SD are more than superficial disorders of the stratum corneum. Instead, the epidermis is substantially altered, with hyperproliferation, excess intercellular and intracellular lipids, interdigitation of the corneal envelope, and parakeratosis (
      • McOsker D.E.
      • Hannon D.P.
      Ultrastructural studies of dandruff-involved scalp tissue.
      ;
      • Warner R.R.
      • Schwartz J.R.
      • Boissy Y.
      • Dawson T.L.
      Dandruff has an altered stratum corneum ultrastructure that is improved with zinc pyrithione shampoo.
      ). In previous work, we have shown that these abnormalities are seen throughout the scalp of affected individuals, not just in areas of flaking, and are improved by treatment with anti-fungal agents, including pyrithione zinc shampoo. Recent technical advances, including improved microbial and analytical techniques (
      • Gemmer C.M.
      • DeAngelis Y.M.
      • Theelen B.
      • Boekhout T.
      • Dawson T.L.
      Fast, noninvasive method for molecular detection and differentiation of Malassezia yeast species on human skin and application of the method to dandruff microbiology.
      ;
      • Batra R.
      • Boekhout T.
      • Guého E.
      • Cabañes F.J.
      • Dawson T.L.
      • Gupta A.K.
      Malassezia Baillon, emerging clinical yeasts.
      ), have provided new insights into the underlying pathology. Based upon the most recent evidence, the etiology of D/SD appears to be dependent upon three factors: sebaceous gland secretions, microfloral metabolism, and individual susceptibility (
      • DeAngelis Y.M.
      • Gemmer C.M.
      • Kaczvinsky J.R.
      • Kenneally D.C.
      • Schwartz J.R.
      • Dawson T.L.
      Three etiologic facets of dandruff and seborrheic dermatitis: Malassezia fungi, sebaceous lipids, and individual sensitivity.
      ;
      • Ro B.I.
      • Dawson T.L.
      The role of sebaceous gland activity and scalp microfloral metabolism in the etiology of seborrheic dermatitis and dandruff.
      ). This paper will describe recent advances in the understanding of these factors, especially the role of the yeast Malassezia. These advances may provide new avenues to effective therapies.

      Discussion

      Role of sebaceous gland activity

      The role of sebaceous gland activity in D/SD etiology is suggested by the observation that common scalp flaking conditions have a strong temporal correlation with sebaceous gland activity. This temporal correlation includes increased incidence during infancy (cradle cap), low incidence after infancy until puberty, increase in adolescence and young adulthood, and a decrease later in life (
      • Ramasastry P.
      • Downing D.T.
      • Pochi R.E.
      • Strauss J.S.
      Chemical composition of human skin surface lipids from birth to puberty.
      ;
      • Cotterill J.A.
      • Cunliffe W.J.
      • Williamson B.
      • Bulusu L.
      Age and sex variation in skin surface lipid composition and sebum excretion rate.
      ;
      • Wheatley V.R.
      The chemistry of sebum.
      ,
      • Dawber R.
      ). In addition, D/SD occur exclusively on skin in areas with high levels of sebum.
      The function of human sebum has been controversial, but recent advances in analytical technology have made some progress possible. Sebum is involved in epidermal development and barrier maintenance (
      • Pilgram G.S.
      • Meulen J.
      • van der Gooris G.S.
      • Koerten H.K.
      • Bouwstra J.A.
      The influence of two azones and sebaceous lipids on the lateral organization of lipids isolated from human stratum corneum.
      ), transporting antioxidants (
      • Theile J.J.
      • Weber S.U.
      • Packer L.
      Sebaceous gland activity is a major physiologic route of vitamin E delivery to the skin.
      ), protection, body odor, and generation of pheromones (
      • Kligman A.M.
      The uses of sebum.
      ). It has also recently become understood that sebum is directly involved in hormonal signaling, epidermal differentiation, and protection from UV (
      • Thiboutot D.
      • Jabara S.
      • McAllister J.M.
      • Sivarajah A.
      • Glilliland K.
      • Cong Z.
      • et al.
      Human skin is a steroidogenic tissue: steroidogenic enzymes and cofactors are expressed in epidermis, normal sebocytes, and an immortalized sebocyte cell line (SEB-1).
      ;
      • Zouboulis C.C.
      Sebaceous gland in human skin – the fantastic future of a skin appendage.
      ).
      Human sebum is a complex mixture of triglycerides, fatty acids, wax esters, sterol esters, cholesterol, cholesterol esters, and squalene (Figure 1) (
      • Stewart M.E.
      • Downing D.T.
      • Pochi P.E.
      • Strauss J.S.
      The fatty acids of human sebaceous gland phosphatidylcholine.
      ;
      • Strauss J.S.
      • Downing D.T.
      • Ebling F.J.
      Sebaceous glands.
      ;
      • Wertz P.W.
      • Michniak B.B.
      Sebum.
      ;
      • Ro B.I.
      • Dawson T.L.
      The role of sebaceous gland activity and scalp microfloral metabolism in the etiology of seborrheic dermatitis and dandruff.
      ). When secreted, sebum consists of triglycerides and esters, which are broken down by microbes into diglycerides, monoglycerides, and free fatty acids. The free fatty acids play a key role in initiation of the irritant response at the base of D/SD. The role of sebaceous secretion also underlies the impact of stress and hormones on D/SD. It is well known that these are affecters of human sebum secretion and therefore impact D/SD (
      • Cotterill J.A.
      • Cunliffe W.J.
      • Williamson B.
      Variation in skin surface lipid composition and sebum excretion rate with time.
      ;
      • Downing D.T.
      • Stewart M.E.
      • Strauss J.S.
      Changes in sebum secretion and the sebaceous gland.
      ;
      • Saint-Léger D.
      Normal and pathologic sebaceous function. Research in a shallow milieu?.
      ).
      Figure thumbnail gr1
      Figure 1Relative composition of human sebum.
      (reprinted from
      • Ro B.I.
      • Dawson T.L.
      The role of sebaceous gland activity and scalp microfloral metabolism in the etiology of seborrheic dermatitis and dandruff.
      )

      Role of Malassezia

      Although they are members of the normal skin flora, yeasts of the genus Malassezia have been known for many years to play a role in human skin diseases, including dandruff, seborrheic dermatitis, pityriasis versicolor, and Malassezia folliculitis, and they may play a role in exacerbation of atopic dermatitis and psoriasis (
      • Gupta A.K.
      • Batra R.
      • Bluhm R.
      • Boekhout T.
      • Dawson T.L.
      Skin diseases associated with Malassezia species.
      ;
      • Batra R.
      • Boekhout T.
      • Guého E.
      • Cabañes F.J.
      • Dawson T.L.
      • Gupta A.K.
      Malassezia Baillon, emerging clinical yeasts.
      ). The importance of fungal species in development of D/SD is supported by the fact that effective treatments include a wide variety of agents whose only common property is their anti-fungal activity. Further, the improvement in flaking following treatment is highly correlated with the reduction in the level of scalp Malassezia (
      • Schwartz J.R.
      • Cardin C.M.
      • Dawson T.L.
      Dandruff and seborrheic dermatitis.
      ). The study of this genus has been complicated by their fastidious culture requirements and a complex series of changes in nomenclature (
      • Batra R.
      • Boekhout T.
      • Guého E.
      • Cabañes F.J.
      • Dawson T.L.
      • Gupta A.K.
      Malassezia Baillon, emerging clinical yeasts.
      ).
      Although the genus has also been called Pityrosporum, that name is no longer preferred. At one time, the members of Malassezia were classified into two species: a lipid-dependent species Malassezia furfur, and a non-lipid-dependent species, M. pachydermatis. More recently, it has been recognized that there are multiple different lipid-dependent species (including M. globosa, M. restricta, M. furfur, M. obtusa, M. slooffiae, M. sympodialis, M. japonica, M. nana, M. dermatis, and M. yamatoensis), in addition to the non-lipid-dependent, primarily zoophilic species, M. pachydermatis (
      • Batra R.
      • Boekhout T.
      • Guého E.
      • Cabañes F.J.
      • Dawson T.L.
      • Gupta A.K.
      Malassezia Baillon, emerging clinical yeasts.
      ). Use of molecular markers is generally required to correctly differentiate between the various lipid-dependent species (
      • Guého E.
      • Midgley G.
      • Guillot J.
      The genus Malassezia with the description of four new species.
      ;
      • Ashbee H.R.
      • Evans E.G.V.
      Immunology of diseases associated with Malassezia species.
      ;
      • Sugita T.
      • Takashima M.
      • Kodama M.
      • Tsuboi R.
      • Nishikawa A.
      Description of a new yeast species, Malassezia japonica, and its detection in patients with atopic dermatitis and healthy subjects.
      ,
      • Sugita T.
      • Tajima M.
      • Ito T.
      • Saito M.
      • Tsuboi R.
      • Mishikawa A.
      Antifungal activities of tacrolimus and azole agents against the eleven currently accepted Malassezia species.
      ;
      • Gupta A.K.
      • Boekhout T.
      • Theelen B.
      • Summerbell R.C.
      • Batra R.
      Identification and typing of Malassezia species by amplified fragment length polymorphism (AFLP) and sequence analyses of the internal transcribed spacer (ITS) and large subunit (LSU) regions of ribosomal DNA.
      ). Using an advanced molecular technique, terminal fragment length polymorphism, we previously identified M. globosa and M. restricta as the predominant species present on the scalp of D/SD sufferers (
      • Gemmer C.M.
      • DeAngelis Y.M.
      • Theelen B.
      • Boekhout T.
      • Dawson T.L.
      Fast, noninvasive method for molecular detection and differentiation of Malassezia yeast species on human skin and application of the method to dandruff microbiology.
      ). The Malassezia yeasts are most common on sebum-rich areas of the body and degrade sebum. Specifically, the organisms contain lipases that hydrolyze triglycerides, freeing specific saturated fatty acids that the yeast requires to proliferate. To demonstrate that Malassezia generated free fatty acids can induce dandruff-like flaking in humans, we applied a marker fatty acid, oleic, to human scalp. Even when Malassezia had been removed from the scalp oleic acid was able to elicit a flaking response in dandruff susceptible individuals (
      • Ro B.I.
      • Dawson T.L.
      The role of sebaceous gland activity and scalp microfloral metabolism in the etiology of seborrheic dermatitis and dandruff.
      ).

      Role of individual susceptibility

      We have shown that a fatty acid metabolite of Malassezia, oleic acid, induces flaking in dandruff-susceptible patients, but not in non-susceptible patients (
      • Ro B.I.
      • Dawson T.L.
      The role of sebaceous gland activity and scalp microfloral metabolism in the etiology of seborrheic dermatitis and dandruff.
      ). This finding provides evidence of role of these fatty acid metabolites in dandruff development and suggests an underlying difference between individuals that predisposes some to the development of dandruff or seborrheic dermatitis. Additionally, immunodeficiency such as acquired immune deficiency syndrome allows excess Malassezia proliferation, resulting in severe D/SD. Physical factors, nutritional disorders, drugs, and neurotransmitter abnormalities are additional aggravating factors. The difference between dandruff-susceptible and non-susceptible individuals remains unclear. Multiple possibilities exist, including innate differences in stratum corneum barrier function, skin permeability, and immune response to free fatty acids or proteins and polysaccharides from Malassezia. Further work will be necessary to fully understand the susceptibility response.

      Initial forays into understanding lipase activity

      Lipases play a key role in the lifestyle of Malassezia species on skin (Figure 2). In order to better understand this role, we isolated a lipase from M. globosa (DeAngelis et al., in press). This protein was sequenced and the corresponding lipase gene (LIP1) was cloned and sequenced. This work was a first step toward a molecular description of lipid metabolism on the scalp and a more complete understanding of the role of microbial metabolism in the etiology of D/SD. Based on the limited activity of LIP1, we thought it likely that additional lipases were present in Malassezia, and that further work would be necessary to delineate the complete metabolic pathway.
      Figure thumbnail gr2
      Figure 2A model of the role of Malassezia lipase-mediated hydrolysis of scalp lipids in the etiology of dandruff and seborrheic dermatitis. Some fatty acids are consumed by the fungal cells, whereas other fatty acids cause scalp irritation.
      (reprinted from
      • DeAngelis Y.M.
      • Saunders C.W.
      • Johnstone K.R.
      • Reeder N.L.
      • Coleman C.G.
      • Kaczvinsky J.R.
      • et al.
      Isolation and expression of a Malassezia globosa lipase gene, LIP1.
      )

      Sequencing of the Malassezia genomes

      Increased understanding of the role of each of the three factors (sebaceous gland activity, microbial flora, and individual susceptibility) in D/SD offers the promise of new approaches to treatment. With this aim, we have been cooperating with an international team to further investigate the biochemistry of Malassezia species implicated in D/SD, including elucidation of the genomes of these organisms. Detailed understanding of the yeast's biochemical adaptations to its unique niche on sebum-rich skin may allow design of treatments specifically directed at altering the levels or action of Malassezia on affected skin.

      The M. globosa genome

      To understand Malassezia biology and elucidate the mechanism of their peculiar lipid dependence, we performed whole-genome sequencing of M. globosa and M. restricta. The M. globosa genome is 9 Mb, the smallest of any known free-living fungi (
      • Dietrich F.S.
      • Voegeli S.
      • Brachat S.
      • Lerch A.
      • Gates K.
      • Steiner S.
      • et al.
      The Ashbya gossypii genome as a tool for mapping the ancient Saccharomyces cerevisiae genome.
      ;
      • Hermida L.
      • Brachat S.
      • Voegeli S.
      • Philippsen P.
      • Primig M.
      The Ashbya genome database (AGD) – a tool for the yeast community and genome biologists.
      ). To properly identify genes, the prediction of protein coding frames was improved by sequencing mRNA transcripts, allowing prediction of 4,289 protein-coding genes. Despite the small number of genes, the genome encodes the metabolic components for glycolysis, the tricarboxylic acid cycle, synthesis of all 20 canonical amino acids and the five nucleic acid bases, among others. The key deficiency is the absence of a fatty acid synthase, likely revealing why most Malassezia species are dependent on fatty acids for growth. In contrast to M. globosa, the available genomes of all other free-living fungi contain fatty acid synthases. The need for Malassezia to assimilate external fatty acids is also reflected in the number of multiple secreted lipases (13) and phospholipases (9). Reverse transcription-PCR and proteomics experiments confirmed the expression of multiple lipase and phospholipase genes on human scalp.
      Of course, the enzymes would need to be extracellular to interact with host sources. We therefore performed proteomics experiments to identify over 50 secreted proteins. Some of the most abundant secreted proteins were, as hypothesized, lipases. In addition, many other secreted proteins were identified, including aspartyl proteases, members of the phospholipase C family, glucose-methanol-choline oxidoreductases, known Malassezia allergens (
      • Chen T-A.
      • Hill P.B.
      The biology of Malassezia organisms and their ability to induce immune responses and skin disease.
      ), cell wall modifying enzymes, and unknown proteins. Because these proteins are secreted, they would be the most likely to interact with skin and would therefore mediate Malassezia pathogenicity and be relevant therapeutic targets.

      Areas of future research

      It will be necessary to conduct significantly more research into Malassezia biology and their interaction with human skin to understand the fundamentals of the interactions. The sequencing of these genomes, in conjunction with the already sequenced human genome, will allow detailed investigation of the metabolic interactions between human skin and Malassezia. As new pathways are elucidated, new intervention targets will arise. This new, groundbreaking research will enable development of new technologies to interrupt D/SD, which are not dependent on and can compliment existing anti-fungal treatments.

      Summary

      Work on the Malassezia genome and biochemistry provides insights into the mechanisms by which fungi adapt to the mammalian skin environment. These genomes will also provide new opportunities to dissect the specific interactions between ubiquitous mammalian commensal fungi and the skin. Deeper understanding of these interactions may well lead to new treatment paradigms and innovative ways to modify the effects of Malassezia species on human and animal health. Currently, anti-fungal treatments are the only effective means to control D/SD. Hopefully, new, more fundamental understanding of the interactions between Malassezia and human skin will enable development of new tools, which manage both the number and the activity of these unique fungi.

      ACKNOWLEDGMENTS

      This work was funded by the Procter & Gamble Company. The international team necessary for this type of work includes, but is not limited to the “Malassezia Research Consortium” (Tom Dawson, Charlie Saunders, Jun Xu, Teun Boekhout, Jim Kronstad, Jacques Guillot, Javier Cabanes, and Aditya K. Gupta), as well as Ray Grant, Angela Fieno, Yvonne DeAngelis, Kevin Johnstone, Nancy Reeder, Ping Hu, Meredith Leland, Tom Keough, Yiping Sun, Bill Begely, and Martin Lacey (at the Procter & Gamble Company), Ross Overbeek, Sveta Gerdes, Michael Fonstein, and Veronica Vonstein (at Integrated Genomics at the time of the work), Russell Sears, Bo Yuan (at The Ohio State University), Jim Kronstad (at the University of British Colombia, CA), Teun Boekhout, Bart Theelen, and Eiko Kurame (at the Central Bureau for Fungal Culture, the CBS, Utrecht, The Netherlands). We also acknowledge Lisa Bosch for help in preparing this paper, and Gil Cloyd for his support.

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