Date Published: January 8, 2015
Publisher: Public Library of Science
Author(s): Aristea Velegraki, Claudia Cafarchia, Georgios Gaitanis, Roberta Iatta, Teun Boekhout, Joseph Heitman.
The fungal genus Malassezia comprises lipid-dependent and lipophilic yeast species that are part of the normal skin microbiota . The 14 species are classified in class Malasseziomycetes in the Ustilaginomycotina of Basidiomycota . Malassezia species can be involved in skin disorders, such as pityriasis versicolor, seborrheic dermatitis, atopic eczema, and folliculitis, and occur at higher population densities on scalps with dandruff than on scalps without dandruff , . Occasionally, invasive infections by Malassezia pachydermatis and lipid-dependent Malassezia spp. occur in neonates, most often in those who are receiving intravenous lipid supplementation, or in immunocompromised patients receiving parenteral nutrition via a catheter. Malassezia spp. have not yet been cultured from the environment, but metagenomics identified Malassezia phylotypes from terrestrial and marine habitats . For instance, Malassezia ribosomal DNA (rDNA) has been reported from soil nematodes , sponges , and rocks . Undeniably, much remains to be discovered about the spectrum of habitats exploited by Malassezia that would advance our knowledge on the ecological relationships between the Malassezia skin biotic community, their hosts, and the environment. The aim of this article is to review and discuss the literature available on the pathogenesis, detection, typing, and treatment of Malassezia infections in humans and animals.
The pathophysiology of Malassezia-caused or Malassezia-exacerbated skin conditions is largely unknown, owing to the complex interactions of this commensal with the skin, an organ that has been on the edge of extreme selection pressure during evolution. In healthy skin, Malassezia yeasts exploit essential nutrients for their growth without inflicting disease (Fig. 1). When this process is perturbed, Malassezia yeasts adapt by modifying the expression of enzymes involved in the acquisition of energy, such as lipases and phospholipases , , and at the same time synthesize an array of bioactive indoles that act through the aryl-hydrocarbon receptor (AhR), which is expressed on almost all cell types found in the epidermis .
Patients under total parenteral nutrition (TPN) and immunocompromised patients with increased length of stay (LOS) in intensive care units are at risk for Malassezia infections. Risk for Malassezia infections is also high in very-low-birth-weight infants (<1500 g) and highest in premature infants . The mechanism of transmission to the infant is vertical or horizontal . After host exposure, the degree of prematurity, the corresponding skin condition, endotracheal intubation, central vascular access, diseases such as necrotizing enterocolitis or focal bowel perforation, and abdominal surgery contribute to colonization. Colonization is further enhanced by the pathogen's virulence factors, including adherence properties that favour colonization and proliferation followed by biofilm formation in central vascular catheters , . These, in conjunction with iatrogenic factors, comprising invasive treatments and use of broad-spectrum antibiotics, parenteral nutrition, and administration of postnatal steroids and gastric acid inhibitors, contribute to the infection processes . Compromised or immature host immunity, delayed diagnosis followed by persistent Malassezia fungemia and subsequent delayed vascular catheter removal, tissue or valve injury, insufficient antifungal dosing, or coinfection may lead to dissemination and occasionally result in poor prognosis. M. pachydermatis, normally present on the skin and in the ear canal of dogs and cats, frequently causes dermatitis and otitis in mammals. However, the pathogenic role of Malassezia in the occurrence of lesions seems to be related to the host immune system as well as to yeast virulence factors , . Particular conditions, such as atopic or seborrheic dermatitis, parasitic infestation, diabetes mellitus in dogs, feline immunodeficiency virus, and feline leukaemia virus infections, and long-term antibiotic use associated with glucocorticoid treatment may predispose to Malassezia overgrowth, usually leading to development of lesions . Additionally, lesions might appear as a consequence of hypersensitivity reaction to yeast allergens or might be prevented by active stimulation of the reticuloendothelial system, as previously shown in dogs infected with Leishmania spp. . Isolation and enumeration of Malassezia cells from clinical specimens remains a challenge because of their lipid dependency. Since the clinical features, laboratory markers, and strategies for patient management do not differ between Candida and Malassezia fungemia, a more accurate etiological diagnosis is needed in high-risk patients by employing lipid-supplemented culture media in the current mycological routine , . For septicaemia, contemporary paediatric aerobic lysis and centrifugation bottles supporting the growth of this yeast are recommended , followed by subculturing on lipid-supplemented media, such as modified Dixon or Leeming and Notman agars. Use of Sabouraud dextrose agar with the addition of a few drops of sterile olive oil does not support growth of all Malassezia spp. . Identification of Malassezia isolates can to some extent be achieved by microbiological and physiological assays , , . However, molecular diagnostic methods are preferred for both strain identification and typing. These may comprise PCR–restriction fragment length polymorphism (RFLP) analysis of the internal transcribed spacer 2 (ITS2) region of rDNA, sequence analysis of the ITS 1+2 regions (including the 5.8S rRNA gene) of rDNA, the 5′ end of the large-subunit (LSU or 26S) rDNA, and the β-tubulin gene, and terminal fragment length polymorphism analysis (tFLP) , , , , –. Recently, matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry (MS) has been used to identify Malassezia isolates , . Direct identification and quantification of Malassezia species from specimens obtained from skin by adhesive transparent dressings using multiplex real-time PCR  also provides reliable identification outcomes. Malassezia systemic infections require prompt identification of the pathogenic agent, removal of the central venous catheter and discontinuation of lipid supplementation, and treatment with liposomal amphotericin B , . On the contrary, topical antifungal agents are adequate for the management of localized skin disease, while extensive disease requires administration of systemic itraconazole or fluconazole , . This is also suitable for Malassezia folliculitis with concomitant modification of predisposing factors such as occlusion or systemic immunosuppresion. For the characteristic inflammatory conditions, seborrheic and atopic dermatitis, the addition of local anti-inflammatory therapy (i.e., corticosteroids or calcineurin inhibitors) is a prerequisite for rapid and effective control of exacerbations. One should always bear in mind that Malassezia yeasts are integral components of the skin microbiota and therefore the therapeutic target should be controlling the Malassezia population with subsequent long-term antifungal treatment, rather than eradicating it. Likewise, the need for extended (>2 months) azole treatment is required for suppression of symptoms in the Malassezia-triggered head and neck variant of atopic dermatitis . Although the in vitro susceptibility testing is not yet standardized for Malassezia spp., the Clinical and Laboratory Standards Institute (CLSI) broth microdilution protocol was adapted by modifying media, time of incubation, and inocula, showing that itraconazole, ketoconazole, and posaconazole are the most effective drugs , .
Over the last few decades, advances in research and technologies have greatly contributed to elucidating the role of Malassezia species in human and animal skin diseases and in human bloodstream infections. Molecular and alternative approaches have provided insights into the identification, taxonomy, and epidemiology of Malassezia species. In particular, PCR-RFLP, random amplified polymorphic DNA (RAPD), AFLP, PCR-single strand conformation polymorphism (SSCP) analysis, multilocus sequence typing (MLST, e.g., of ITS, IGS, chs2, and RNA polymerase 1 and 2), and MALDI-TOF MS resulted in the accurate identification and genotyping of Malassezia strains from humans or animals, thus resolving questions related to the geographical distribution of the infection agents and the characterization of strains causing outbreaks , . Nevertheless, these studies showed that the diversity within a single Malassezia species can more likely be attributed to a high degree of evolution driven by ecology, host adaptation, and pathogenicity. In particular, the pathogenic role of Malassezia yeasts seems to be related to changes in the normal physical, chemical, or immunological processes in the skin, which may enhance or down-regulate the molecular production of yeast virulence factors or antigens , . The chemical composition of host epidermis seems to play a pivotal role in influencing the pathogenic or commensal phenotype of Malassezia yeasts by selecting different genetic populations with specific physiological requirements, different cell wall compositions, and different antifungal susceptibility profiles. In addition, molecular and physiological studies suggest the possibility of sexual or parasexual reproduction that might have a role in the process of adaptation of different Malassezia genotypes on different hosts or skin sites. As a consequence, antifungal therapy in Malassezia infections requires careful appraisal of drugs chosen, especially in cases of unresponsiveness to the treatment or recurrent infections. So far, restoring the epidermal-barrier function and avoiding immunoglobulin E (IgE) sensitization seems to be useful for the prevention and treatment of skin diseases complicated by Malassezia, even if antifungal therapy remains the main effective treatment in the near future. Alternative future treatments seem to be the use of selected cell-penetrating peptides that are harmless for mammalian cells but have antifungal activity, as shown for Malassezia otitis in dogs .