Head and neck dermatitis is exacerbated by Malassezia furfur colonization, skin barrier disruption, and immune dysregulation.

Introduction & objectives: Head and neck dermatitis (HND) is a refractory phenotype of atopic dermatitis (AD) and can be a therapeutic challenge due to lack of responsiveness to conventional treatments. Previous studies have suggested that the microbiome and fungiome may play a role in inducing HND, but the underlying pathogenic mechanisms remain unknown. This study aimed to determine the link between HND and fungiome and to examine the contribution of Malassezia furfur. Materials and methods: To identify the effect of the sensitization status of M. furfur on HND, 312 patients diagnosed with AD were enrolled. To elucidate the mechanism underlying the effects of M. furfur, human keratinocytes and dermal endothelial cells were cultured with M. furfur and treated with Th2 cytokines. The downstream effects of various cytokines, including inflammation and angiogenesis, were investigated by real-time quantitative PCR. To identify the association between changes in lipid composition and M. furfur sensitization status, D-squame tape stripping was performed. Lipid composition was evaluated by focusing on ceramide species using liquid chromatography coupled with tandem mass spectrometry. Results: Increased sensitization to M. furfur was observed in patients with HND. Additionally, sensitization to M. furfur was associated with increased disease severity in these patients. IL-4 treated human keratinocytes cultured with M. furfur produced significantly more VEGF, VEGFR, IL-31, and IL-33. IL-4/M. furfur co-cultured dermal endothelial cells exhibited significantly elevated VEGFR, TGF-ß, TNF-α, and IL-1ß levels. Stratum corneum lipid analysis revealed decreased levels of esterified omega-hydroxyacyl-sphingosine, indicating skin barrier dysfunction in HND. Finally, M. furfur growth was inhibited by the addition of these ceramides to culture media, while the growth of other microbiota, including Cutibacterium acnes, were not inhibited. Conclusions: Under decreased levels of ceramide in AD patients with HND, M. furfur would proliferate, which may enhance pro-inflammatory cytokine levels, angiogenesis, and tissue remodeling. Thus, it plays a central role in the pathogenesis of HND in AD.

Effects of Ultra-Weak Fractal Electromagnetic Signals on Malassezia furfur.

Malassezia spp. are dimorphic, lipophilic fungi that are part of the normal human cutaneous commensal microbiome. However, under adverse conditions, these fungi can be involved in various cutaneous diseases. In this study, we analysed the effect of ultra-weak fractal electromagnetic (uwf-EMF) field exposure (12.6 nT covering 0.5 to 20 kHz) on the growth dynamics and invasiveness of M. furfur. The ability to modulate inflammation and innate immunity in normal human keratinocytes was also investigated. Using a microbiological assay, it was possible to demonstrate that, under the influence of uwf-EMF, the invasiveness of M. furfur was drastically reduced (d = 2.456, p < 0.001), while at the same time, its growth dynamic after 72 h having been in contact with HaCaT cells both without (d = 0.211, p = 0.390) and with (d = 0.118, p = 0.438) uwf-EM exposure, were hardly affected. Real-time PCR analysis demonstrated that a uwf-EMF exposure is able to modulate human-ß-defensin-2 (hBD-2) in treated keratinocytes and at the same time reduce the expression of proinflammatory cytokines in human keratinocytes. The findings suggest that the underlying principle of action is hormetic in nature and that this method might be an adjunctive therapeutic tool to modulate the inflammatory properties of Malassezia in related cutaneous diseases. The underlying principle of action becomes understandable by means of quantum electrodynamics (QED). Given that living systems consist mainly of water and within the framework of QED, this water, as a biphasic system, provides the basis for electromagnetic coupling. The oscillatory properties of water dipoles modulated by weak electromagnetic stimuli not only affect biochemical processes, but also pave the way for a more general understanding of the observed nonthermal effects in biota.

Malassezia restricta-mediated Lipoperoxidation: A Novel Trigger in Dandruff.

Dandruff is a common scalp disorder with multiple microbial and host-related factors contributing to its aetiology, including alterations in scalp sebum. Despite existing evidence that the yeast Malassezia restricta plays a key role in the onset of dandruff, the interplay of these factors is poorly understood. Recently, squalene monohydroperoxide and malondialdehyde were established as biomarkers of dandruff-afflicted scalp, highlighting the role of sebum lipoperoxidation in the triggering and maintenance of dandruff, although its mechanism of action is unknown. The current study provides evidence that M. restricta mediates sebum peroxidation, leading to production of squalene monohydroperoxide and malondialdehyde. Furthermore, in vitro data show that these lipoperoxidation products act on epidermal cells and alter the skin barrier. These results support the role of Malassezia restricta-induced lipoperoxides as triggers of dandruff, which suggests that blocking their production could be a novel anti-dandruff treatment approach.

Otitis externa caused by Malassezia slooffiae complicated with mastoiditis: A case report.

Herein, we report a case of otitis externa caused by Malassezia slooffiae complicated with mastoiditis. A 70-year-old male complained of fever and severe otorrhea from left external auditory canal 2 months after undergoing a craniotomy to remove a hematoma. He had right-sided paralysis and undertook bed rest. Brain computed tomography revealed continuous fluid accumulation in the left mastoid air cells and middle ear from left external auditory canal in addition to leukocytosis and increased C-reactive protein level. The tympanic membrane was severely swelling. These results indicated the presence of otitis media and mastoiditis. Otorrhea culture showed large amounts of M. slooffiae. The administration of liposomal amphotericin B (L-AMB), the irrigation of external auditory canal with normal saline, and the application of topical ketoconazole ointment were started. The administration of L-AMB for 8 weeks and voriconazole, which was switched from L-AMB, for 4 weeks ameliorated his infection and he was transferred to another hospital to receive rehabilitation. From these results and his clinical course, the diagnosis of otitis externa caused by Malassezia slooffiae complicated with mastoiditis was made. And the possibility of the contamination by M. slooffiae was very low. Clinicians should be aware that M.slooffiae can provoke otological infections since M. slooffiae is the most common Malassezia sp. in external auditory canal.

Efficacy of a Silver-Based Shampoo for Treatment of Canine Malassezia: A Pilot Study.

Malassezia pachydermatis is a commensal of canines associated with Malassezia dermatitis. Consensus guidelines recommend topical and/or systemic treatment, but resistance to antifungals has been reported. The objective of this pilot study was to determine the efficacy of a 0.003% colloidal silver nanoparticle-based shampoo in the treatment of canine Malassezia dermatitis. Dogs were included based on compatible history, presentation, and at least one positive cytology. Fourteen privately owned dogs were bathed every 48 hr for up to 28 days, allowing 5-10 min of contact time. The mean Malassezia organisms for 10 oil immersion fields at each Malassezia dermatitis-affected body area was recorded at days 0 and 14. Dogs positive on day 14 had cytologies performed on day 28. Eleven dogs (78.6%) were cytologically negative by day 28. Nine (81.8%) of these were negative by day 14. One dog (7.14%) had partial resolution (negative in 3/4 Malassezia dermatitis areas) by day 28. These results suggest that silver nanoparticle-based shampoo may be effective in the treatment of canine Malassezia dermatitis. Larger, controlled studies are needed to further investigate efficacy, optimal concentration, and ideal application frequency.

Malassezia spp. and Candida spp. from patients with psoriasis exhibit reduced susceptibility to antifungals.

INTRODUCTION: Psoriasis is a chronic inflammatory disease that affects over 125 million people worldwide. Many studies have shown the importance of the microbiome for psoriasis exacerbation. AIM: Explore the fungal load and species composition of cultivable yeasts on the skin of psoriatic patients (PP) and healthy volunteers living in a tropical area and evaluate the susceptibility to antifungals. METHODOLOGY: A cross-sectional study with 61 participants (35 patients and 26 healthy controls) was performed during August 2018 and May 2019. Clinical data were collected from patient interviewing and/or medical records review. Samples were collected by swabbing in up to five anatomic sites. Suggestive yeast colonies were counted and further identified by phenotypical tests, PCR-REA, and/or MALDI-TOF. Susceptibility of Malassezia spp. and Candida spp. to azoles, terbinafine, and amphotericin B was evaluated by broth microdilution. RESULTS: Nearly 50% of the patients had moderate to severe psoriasis, and plaque-type psoriasis was the most common clinical form. Yeast colonies count was significantly more abundant among PP than healthy controls. Malassezia and Candida were the most abundant genus detected in all participants. Higher MIC values for ketoconazole and terbinafine were observed in Malassezia strains obtained from PP. Approximately 42% of Candida isolates from PP showed resistance to itraconazole in contrast to 12.5% of isolates from healthy controls. MIC values for fluconazole and amphotericin B were significantly different among Candida isolates from PP and healthy individuals. CONCLUSION: This study showed that Malassezia and Candida strains from PP presented higher MIC values to widespread antifungal drugs than healthy individuals.

The Interkingdom Interaction with Staphylococcus Influences the Antifungal Susceptibility of the Cutaneous Fungus Malassezia.

The skin is a dynamic ecosystem on which diverse microbes reside. The interkingdom interaction between microbial species in the skin microbiota is thought to influence the health and disease of the skin although the roles of the intra- and interkingdom interactions remain to be elucidated. In this context, the interactions between Malassezia and Staphylococcus, the most dominant microorganisms in the skin microbiota, have gained attention. This study investigated how the interaction between Malassezia and Staphylococcus affected the antifungal susceptibility of the fungus to the azole antifungal drug ketoconazole. The susceptibility was significantly decreased when Malassezia was co-cultured with Staphylococcus. We found that acidification of the environment by organic acids produced by Staphylococcus influenced the decrease of the ketoconazole susceptibility of M. restricta in the co-culturing condition. Furthermore, our data demonstrated that the significant increased ergosterol content and cell membrane and wall thickness of the M. restricta cells grown in the acidic environment may be the main cause of the altered azole susceptibility of the fungus. Overall, our study suggests that the interaction between Malassezia and Staphylococcus influences the antifungal susceptibility of the fungus and that pH has a critical role in the polymicrobial interaction in the skin environment.

An Up-to-Date Approach to the Management of Seborrheic Dermatitis.

Seborrheic dermatitis (SD) is a chronic, relapsing, inflammatory dermatosis with ambiguous pathophysiology of overcolonization of Malassezia combined with predisposing factors including sebocyte activity, impaired immunity with diminished T-cell responses and activation of complements, disruption of epidermal barrier integrity and skin microbiota, and environmental influences.

Complement and Fungal Dysbiosis as Prognostic Markers and Potential Targets in PDAC Treatment.

Pancreatic ductal adenocarcinoma (PDAC) is still hampered by a dismal prognosis. A better understanding of the tumor microenvironment within the pancreas and of the factors affecting its composition is of utmost importance for developing new diagnostic and treatment tools. In this context, the complement system plays a prominent role. Not only has it been shown to shape a T cell-mediated immune response, but it also directly affects proliferation and apoptosis of the tumor cells, influencing angiogenesis, metastatic spread and therapeutic resistance. This makes complement proteins appealing not only as early biomarkers of PDAC development, but also as therapeutic targets. Fungal dysbiosis is currently the new kid on the block in tumorigenesis with cancer-associated mycobiomes extracted from several cancer types. For PDAC, colonization with the yeast Malassezia seems to promote cancer progression, already in precursor lesions. One responsible mechanism appears to be complement activation via the lectin pathway. In the present article, we review the role of the complement system in tumorigenesis, presenting observations that propose it as the missing link between fungal dysbiosis and PDAC development. We also present the results of a small pilot study supporting the crucial interplay between the complement system and Malassezia colonization in PDAC pathogenesis.

Establishment of a gene recombination method for a major human skin commensal fungus, Malassezia restricta, using Agrobacterium tumefaciens-mediated gene transfer system.

Malassezia restricta is the most predominant fungus in the microbiome of human skin. This microorganism can cause or exacerbate Malassezia-associated skin dermatitis, seborrheic dermatitis, atopic dermatitis, and pityriasis versicolor. The virulence factors of M. restricta have not been analyzed because a gene recombination system has not been developed. In this study, we established an Agrobacterium tumefaciens-mediated gene transfer (ATMT) system, optimized for generating gene-deficient mutants of M. restricta. A mutant of FKB1 gene, which encodes the FKBP12 protein that binds to the calcineurin inhibitor tacrolimus, was generated using the ATMT system. Subsequently, the FKB1 gene was reintroduced into the FKB1 gene-deficient mutant for obtaining a gene-complemented strain. The wild-type strain of M. restricta was sensitive to tacrolimus, whereas the FKB1 gene-deficient mutant was resistant to tacrolimus; the phenotypic drug susceptibility in the mutant was restored by reintroducing the FKB1 gene. Contrastingly, the FKB1 gene-deficient mutant was not resistant to cyclosporine A, which also inhibits calcineurin by binding to cyclophilin A. The gene recombination system for M. restricta will facilitate in elucidating the molecular mechanisms causing Malassezia-associated dermatitis.

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

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, 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 diseased groups, in lesional and non-lesional skin sites, as 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 inflammatory cell infiltration 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.

Malassezia overgrowth in dogs in northern Italy: frequency, body distribution, clinical signs and effects of pharmacologic treatments.

The present study describes Malassezia populations in clinically healthy dogs (HD) and dogs with Malassezia overgrowth (MO), and evaluates the correlation with clinical signs and previous treatments. Thirteen clinically HD and 84 dogs with MO were enrolled. Clinical history and previous treatments were recorded. After a complete physical and dermatological examination, Canine Atopic Dermatitis Extent and Severity Index_03 scores were calculated. Samples for cytology and mycological cultures were obtained from four body regions and from skin lesions. Malassezia overgrowth was diagnosed by cytology. A global score (GS) for quantitative evaluation of the population of Malassezia was calculated. In dogs with MO, the highest frequency of yeast detection was found in skin lesions (82%, P < 0.001). Sum of GS (GSs) obtained from dogs with MO (68, 0­621) was significantly higher compared to those of HD (3, 0­48, P < 0.001). GSs in dogs previously treated with antibiotics (312.5, 30­975) was significantly higher compared to those of dogs that not have received antibiotics (80, 0­975, P = 0.015). No difference was found between dogs treated and those not treated with steroids.

Polygalaxanthone III, an Active Ingredient in Polygala japonica Houtt., Repaired Malassezia-Stimulated Skin Injury via STAT3 Phosphorylated Activation.

Malassezia is a genus of commensal and lipid-dependent yeasts in human skin which also have a pathogenic lifestyle associated with several common skin disorders such as atopic dermatitis and eczema. Symptoms include red, itchy, and inflamed skin. We studied the growth characteristics and biochemical analyses of M. furfur which showed that the protein contents were greater in extracts taken at 24 h. These were then used to infect C57BL/6 mice, resulting in skin rupture. Polygalaxanthone III (POL), a more effective anti-inflammatory ingredient in Polygala japonica Houtt., was applied externally to the ulceration and successfully healed the wounds quickly. POL could not inhibit Malassezia activity as tested by the inhibition zone test, but affected the formation of lipid droplets in HaCaT cells. The wound-healing molecular mechanisms may be involved in the STAT3 pathway according to the Western blot results of skin tissues. Malassezia's role in skin health is far from certain, and there is no clear solution, so understanding the development of Malassezia-associated skin diseases in general and seeking solutions are very important.

Identification of Malassezia globosa as a Gastric Fungus Associated with PD-L1 Expression and Overall Survival of Patients with Gastric Cancer.

Background: Microbiotas affected the prognosis of cancer patients by regulating programmed death ligand-1 (PD-L1) expression. However, the relationship between gastric fungi and PD-L1 expression is still unclear in gastric cancer (GC). We aimed at exploring the association of gastric fungi with PD-L1 expression and overall survival in GC. Methods: A total of 61 GC patients were divided into the two groups based on the PD-L1 combined positive scores (CPS). Fungal profiling was performed by internal transcribed spacer rDNA sequencing, and the survival analyses were performed by Kaplan-Meier curves. Results: We observed a taxonomic difference of fungi between the PD-L1-High (CPS ≥ 10) and PD-L1-Low group (CPS < 10) by principal coordinates analysis (PCoA) (P = 0.014 for Bray-Curtis and P = 0.042 for Jaccard). Malassezia had a higher abundance in the PD-L1-High group compared to the PD-L1-Low group (P = 0.045). Malassezia globosa elevated significantly in the PD-L1-High group. GC patients with PD-L1 low expression and low abundance of Malassezia globosa had a longer overall survival (OS) than others (P = 0.047). Malassezia globosa was associated with PD-L1 expression (Odds Ratio = 3.509, 95% Confidence Interval: 1.056-11.656, P = 0.040). Malassezia globosa was associated with the tumor size (P = 0.031) and PD-L1 status (P = 0.024). GC patients with a high abundance of Malassezia globosa had shorter OS than others (P = 0.028). Malassezia globosa was an independent factor (Hazard Ratio = 3.080, 95% Confidence Interval: 1.140-8.323, P = 0.027) for OS after adjusting for tumor stage. Malassezia globosa was figured out to be associated with- fatty acid and lipid biosynthesis and degradation via LIPASYN pathway. Conclusions. Malassezia globosa was identified as a PD-L1 expression-associated gastric fungus and associated with OS of GC patients, which calls for more studies to further explore its potential in PD-L1/PD-1 targeted immunotherapy.

Taxonomy of Pathogenic Yeasts Candida, Cryptococcus, Malassezia, and Trichosporon.

This review describes the changes in yeast species names in the previous decade. Several yeast species have been reclassified to accommodate the "One fungus=One name" (1F=1N) principle of the Code. As the names of medically important yeasts have also been reviewed and revised, details of the genera Candida, Cryptococcus, Malassezia, and Trichosporon are described in Section 3, along with the history of name changes. Since the phylogenetic positions of Candida species in several clades have not been clarified, revision of this species has not been completed. Among the species that remain unrevised despite their importance in the medical field, we propose the transfer of six Candida species to be reclassified in the Nakaseomyces clade, including Nakaseomyces glabratus and Nakaseomyces nivalensis.

Malassezia Folliculitis following Triple Therapy for Cystic Fibrosis.

Triple-combination therapy with elexacaftor, tezacaftor and ivacaftor has been recently approved for cystic fibrosis patients with at least one F508del mutation in the transmembrane conductance regulator of the cystic fibrosis gene. Among the adverse events of elexacaftor, tezacaftor and ivacaftor, the cutaneous ones have been rarely reported, mainly dealing with urticarial-like rashes. On this topic, we report two cases of Malassezia folliculitis following triple therapy administration in two young females. In the first patient, a papulopustular rush appeared before the folliculitis while in the second patient it was not preceded by other skin manifestations. The diagnosis was confirmed both by dermoscopy and histology. The prompt response to systemic antimycotic drugs provided further evidence for the causative role of Malassezia, requiring no discontinuation of cystic fibrosis therapy. We could hypothesize that the triple regimen treatment may induce changes in the skin microbiome, potentially able to favor colonization and proliferation of Malassezia species. Physicians should be aware of such associations to allow prompt diagnosis and early interventions, avoiding useless drug removal.

Many ways, one microorganism: Several approaches to study Malassezia in interactions with model hosts.

Malassezia, a lipophilic and lipid-dependent yeast, is a microorganism of current interest to mycobiologists because of its role as a commensal or pathogen in health conditions such as dermatological diseases, fungemia, and, as discovered recently, cancer and certain neurological disorders. Various novel approaches in the study of Malassezia have led to increased knowledge of the cellular and molecular mechanisms of this yeast. However, additional efforts are needed for more comprehensive understanding of the behavior of Malassezia in interactions with the host. This article reviews advances useful in the experimental field for Malassezia.

Malassezia: A Commensal, Pathogen, and Mutualist of Human and Animal Skin.

Identified in the late nineteenth century as a single species residing on human skin, Malassezia is now recognized as a diverse genus comprising 18 species inhabiting not only skin but human gut, hospital environments, and even deep-sea sponges. All cultivated Malassezia species are lipid dependent, having lost genes for lipid synthesis and carbohydrate metabolism. The surging interest in Malassezia results from development of tools to improve sampling, culture, identification, and genetic engineering, which has led to findings implicating it in numerous skin diseases, Crohn disease, and pancreatic cancer. However, it has become clear that Malassezia plays a multifaceted role in human health, with mutualistic activity in atopic dermatitis and a preventive effect against other skin infections due to its potential to compete with skin pathogens such as Candida auris. Improved understanding of complex microbe-microbe and host-microbe interactions will be required to define Malassezia's role in human and animal health and disease so as to design targeted interventions.

[Malassezia Display a Hyphae-like "Spaghetti-and-Meatballs" Configuration in Keratotic Plugs].

Malassezia are lipophilic yeasts in the skin microbiome that abundantly colonize all parts of human skin except for the soles of the feet. Fungal microbiome analysis of keratotic plugs from the noses of 10 healthy individuals identified Malassezia restricta as the predominant species, followed by Malassezia globosa. Malassezia hyphae were observed in 5 of the 10 individuals. The hyphae were curved and thick-walled with spherical thick-walled and grouped blastoconidia, described as a "spaghetti-and-meatballs" configuration. In this study, we observed Malassezia hyphae in keratotic plugs of healthy subjects, although abundant Malassezia hyphae have previously only been observed in lesional sites of patients with pityriasis versicolor.