Erratum to: The Interplay Between NSAIDs and Candida albicans on the Gastrointestinal Tract of Guinea Pigs

Trichophyton rubrum is an anthropophilic species that is the most frequent etiologic agent of human dermatophytosis throughout the world. No teleomorph has been identified for T. rubrum strains. This study used PCR analysis to confirm the presence of a mating type locus in the genome of Japanese isolates of T. rubrum. To clarify the epidemiological and ecological characteristics of this fungus, mating type sequences were tested for correlation of MAT genotype to mating type. This study examined clinical isolates of T. rubrum that had been obtained from 206 human cases of tinea pedis and tinea unguium in Japan, including those from Fukuoka (29 strains), Gifu (23 strains), Kanazawa (63 strains), and Tokyo (91 strains), along with 10 isolates derived from 10 cases of canine dermatophytosis. PCR detected the presence of MAT1-1 in all of the human and animal isolates. Therefore, all isolates examined were expected to react as (?) type on the mating test and not as (+) type.     

Trichophyton rubrum is Inhibited by Free and Nanoparticle Encapsulated Curcumin by Induction of Nitrosative Stress after Photodynamic Activation

Antimicrobial photodynamic inhibition (aPI) utilizes radical stress generated from the excitation of a photosensitizer (PS) with light to destroy pathogens. Its use against Trichophyton rubrum, a dermatophytic fungus with increasing incidence and resistance, has not been well characterized. Our aim was to evaluate the mechanism of action of aPI against T. rubrum using curcumin as the PS in both free and nanoparticle (curc-np) form. Nanocarriers stabilize curcumin and allow for enhanced solubility and PS delivery. Curcumin aPI, at optimal conditions of 10 μg/mL of PS with 10 J/cm² of blue light (417 ± 5 nm), completely inhibited fungal growth (p<0.0001) via induction of reactive oxygen (ROS) and nitrogen species (RNS), which was associated with fungal death by apoptosis. Interestingly, only scavengers of RNS impeded aPI efficacy, suggesting that curcumin acts potently via a nitrosative pathway. The curc-np induced greater NO^• expression and enhanced apoptosis of fungal cells, highlighting curc-np aPI as a potential treatment for T. rubrum skin infections.     

Monocyte-Derived Dendritic Cells from Patients with Dermatophytosis Restrict the Growth of Trichophyton rubrum and Induce CD4-T Cell Activation

Dermatophytes are the most common agents of superficial mycoses that are caused by mold fungi. Trichophyton rubrum is the most common pathogen causing dermatophytosis. The immunology of dermatophytosis is currently poorly understood. Recently, our group investigated the interaction of T. rubrum conidia with peritoneal mouse macrophages. We found that macrophages phagocytose T. rubrum conidia resulted in a down-modulation of class II major histocompatibility complex (MHC) antigens and in the expression of co-stimulatory molecules. Furthermore, it induced the production of IL-10, and T. rubrum conidia differentiated into hyphae that grew and killed the macrophages after 8 hrs of culture. This work demonstrated that dendritic cells (DCs) and macrophages, from patients or normal individuals, avidly interact with pathogenic fungus T. rubrum. The dermatophyte has two major receptors on human monocyte-derived DC: DC-SIGN and mannose receptor. In contrast macrophage has only mannose receptor that participates in the phagocytosis or bound process. Another striking aspect of this study is that unlike macrophages that permit rapid growth of T. rubrum, human DC inhibited the growth and induces Th activation. The ability of DC from patients to interact and kill T. rubrum and to present Ags to T cells suggests that DC may play an important role in the host response to T. rubrum infection by coordinating the development of cellular immune response.     

Increase in Resistance to Fluconazole and Itraconazole in Trichophyton rubrum Clinical Isolates by Sequential Passages In Vitro under Drug Pressure

Trichophyton rubrum, an anthropophilic dermatophyte fungus, is the predominant causative agent of superficial skin infections in human population. There are only scanty reports on drug susceptibility profiling of T. rubrum. Neither mechanisms for drug resistance development nor correlation between in vitro drug susceptibility and in vivo response to treatment is known for that species. In this study, changes in the in vitro susceptibilities to fluconazole (FLZ) and itraconazole (ITZ) among thirty T. rubrum clinical strains subjected to sequential passages in the presence or absence of the azoles were investigated. Each strain was passaged 12 times at 4-week intervals as three parallel cultures, maintained on a drug-free medium (1), and a medium containing FLZ (2) or ITZ (3) at subinhibitory concentrations. Susceptibility to FLZ and ITZ of the original strain and its 3 subcultures was determined by microdilution method. The MIC values of the two azoles remained unaltered for all T. rubrum strains tested, after 12 passages on a drug-free medium. Among the strains grown with FLZ, an increase in the MICs of FLZ and ITZ was noted in 17 (56.7 %) and 19 (63.3 %) strains, respectively. Increased MICs of ITZ and FLZ were demonstrated for 24 (80 %) and 20 (66.7 %) strains that were propagated with ITZ. The results indicate the capacity of T. rubrum to develop resistance toward the azoles after prolonged exposure to these drugs. Resistance of T. rubrum to azoles plays an important role in therapy failures and consequently contributes to persistence and chronicity of the infections.     

<Emphasis Type="Italic">Trichophyton rubrum</Emphasis> Infection Characterized by Majocchi’s Granuloma and Deeper Dermatophytosis: Case Report and Review of Published Literature

Infections caused by Trichophyton rubrum are very common in dermatological disease. It most often appears as superficial cutaneous mycosis, such as tinea manuum, tinea pedis, and tinea corporis. However, deep infection caused by T. rubrum was rarely reported. We describe a case of mixed type of deep infection caused by T. rubrum in a 45-year-old man with no significant immunodeficiency. This patient had a history of onychomycosis on the toenails without regular treatment for nearly 6 years. And, he had erythema, papule, and nodules on the submandibular area, neck, and chest for almost 1 year. After treated with intravenous infusion of cefotiam for 2 weeks, the lesion aggravated. The fungal direct microscopic examination of pyogenic fluid was positive, and the fungal cultures that produced reddish-brown and yellow pigment showed cottony, wooly, and white colony. After the DNA sequencing, it was identified as T. rubrum. We gave the patient oral terbinafine 250 mg per day and bifonazole cream for external use. Six months later, the patient’s skin lesion was disappeared, and healthy nail growth was seen in two-thirds of nail bed. The terbinafine is effective against deep infection caused by T. rubrum.     

Human primary epidermal organoids enable modeling of dermatophyte infections

Technology of generating human epidermal derivatives with physiological relevance to in vivo epidermis is continuously investigated for improving their effects on modeling of human natural dermatological status in basic and clinical studies. Here, we report a method of robust establishment and expansion of human primary epidermal organoids (hPEOs) under a chemically defined condition. hPEOs reconstruct morphological, molecular, and functional features of human epidermis and can expand for 6 weeks. Remarkably, hPEOs are permissive for dermatophyte infections caused by Trichophyton Rubrum (T. rubrum). The T. rubrum infections on hPEOs reflect many aspects of known clinical pathological reactions and reveal that the repression on IL-1 signaling may contribute to chronic and recurrent infections with the slight inflammation caused by T. rubrum in human skin. Thus, our present study provides a new insight into the pathogenesis of T. rubrum infections and indicates that hPEOs are a potential ex vivo model for both basic studies of skin diseases and clinical studies of testing potential antifungal drugs.Subject terms: Skin stem cells, Infection     

The Changing Face of Dermatophytic Infections Worldwide

Dermatophytes evolve along with the geography and socioeconomic conditions. Epidermophyton floccosum, Microsporum audouinii and Trichophyton schoenleinii acted as the major pathogens of superficial fungal diseases 100 years ago, but their frequency decreased dramatically since the middle of the twentieth century and they are limited to some less-developed countries nowadays; meanwhile, frequency of Trichophyton rubrum, Trichophyton interdigitale, Trichophyton tonsurans and Microsporum canis increased gradually, and these fungi have become the major species globally. Some other dermatophytes, i.e., Trichophyton violaceum, Trichophyton verrucosum and Microsporum ferrugineum, are mainly endemic in some parts of Africa, Asia and Europe. At present, T. rubrum is the leading pathogen for skin and nail fungal infections, whereas M. canis, T. tonsurans and T. violaceum present as the predominant dermatophytes involved in tinea capitis. Population mobility, changes in human lifestyle and advents of antifungal drugs will continually drive the dermatophyte evolution in the skin microenvironment. Comprehensive observation is needed to better understand this kind of organisms and prospect the trends of their changes in future.     

Ginnalin B induces differentiation markers and modulates the proliferation/differentiation balance via the upregulation of NOTCH1 in human epidermal keratinocytes

The red maple and sugar maple (Acer rubrum and A. saccharum, respectively) contain acertannins (ginnalins and maplexins), galloylated derivatives of 1,5-anhydro-d-glucitol (1,5-AG, 1). These compounds have a variety of potential medicinal properties and we have shown that some of them promote the expression of ceramide synthase 3. We now report on the beneficial effects of ginnalin B, (6-O-galloyl-1,5-AG, 5), leading to acceleration of skin metabolism and reduction of the turnover time. Ginnalin B dose-dependently increased the relative amount of keratin 10, keratin 1, and filaggrin gene, with maximal increase of 1.7-, 2.9, and 5.2-fold at 100 μM, respectively. The validation study showed that it had superior capacity to induce multiple stages of keratinocyte differentiation and significantly elevated the immunostaining site of keratin 10 and filaggrin in a 3-dimensional cultured human skin model, by 1.2 and 2.8-fold, respectively. Furthermore, ginnalin B caused the arrest of proliferation at the G₀/G₁ phase but it did not induce apoptotic cell death in normal human keratinocytes. Molecular studies revealed that ginnalin B up-regulated the levels of NOTCH1 and a concomitant increase p21 expression. Ginnalin B, therefore, represents a new class of promising functional and medical cosmetic compound and it could contribute to the maintenance of homeostasis of the epidermis.     

Chlamydospores of Rhizopus microsporus var. rhizopodiformis in Tissue of Pulmonary Mucormycosis

Hyphae are usually the only fungal elements found in tissue of mucormycosis, and other fungal elements are quite rarely encountered. We found chlamydospores in bronchial lumina in autopsied tissue of pulmonary mucormycosis of a diabetic patient. Chlamydospores are thick-walled, asexually produced spores arising from the modification of a hyphal segment. This is the first histologic demonstration of chlamydospores in mucormycosis in which the causative fungus is culturally identified to species level. Rhizopus microsporus var. rhizopodiformis was isolated from the present autopsied pulmonary tissue. A literature review of human infection by this fungus found 27 cases with histopathologic evidence.     

In vitro susceptibility to antimycotic drug undecanoic acid,a medium-chain fatty acid,is nutrient-dependent in the dermatophyte Trichophyton rubrum

The antimycotic activity of fatty acids has long been known, and their presence in human skin and sweat appears to protect the host against superficial mycoses. Undecanoic acid is a medium-chain fatty acid that has been used in the treatment of dermatophytoses in humans. In this study, we selected one Trichophyton rubrum undecanoic acid-resistant strain that showed a marked reduction in its capacity to grow on human nail fragments, which correlated with the reduced activity of secreted keratinolytic proteases. Moreover, the susceptibility of T. rubrum to undecanoic acid is also dependent on the carbon source utilized by both control and resistant strains. The growth of the control strain was strongly inhibited by undecanoic acid in Sabouraud medium or in cultures supplemented with low-fat milk, whereas it was ineffective when the cultures were supplemented with Tween 20 or keratin as the carbon source, suggesting that nutrient conditions are crucial in establishing a susceptibility to antifungal drugs, which is helpful for the isolation and characterization of resistant strains, and in the screening for new antifungal drugs.     

Effects of salinity, pH, organic solutes, anaerobic conditions, and the presence of other microbes on production and survival of Lagenidium giganteum (Oomycetes: Lagenidiales) zoospores

The effects of several environmental factors on the production of viable zoospores by Lagenidium giganteum were determined by counts of germlings produced after induction of zoosporogenesis by suspension of mycelium in various substances. NaCl at a concentration of 0.6 g/liter virtually eliminated zoosporogenesis. At 0.2 g/liter NaCl there was a significant reduction in four of the five fungal isolates tested. Transmission of fungus between mosquito larvae at 0.8 g/liter NaCl suggests that estimates of solute effects from in vitro studies are exaggerated. Zoosporogenesis took place from pH 4.5 to 8.4 by three isolates and from 4.5 to 8 by two other isolates (±0.2). Anaerobic conditions halted zoosporogenesis. Reintroduction of oxygen within 7 days allowed the process to resume, but with reduced production for each day under anaerobic conditions. Five species of bacteria inhibited zoosporogenesis at concentrations of 10⁷–10⁸ cells/ml. The yeast, Saccharomyces cerevisiae, was inhibitory at 10⁶ cells/ml. Three sugars, a sugar alcohol, three amino acids, and peptone all reduced zoosporogenesis at levels that generally correlated positively with their nutritional values for the fungus. Peptone, which can support lush vegetative growth of L. giganteum in the absence of other nutrients, was far more effective in inhibiting zoosporogenesis than the other solutes.     

The human fungal pathogen Malassezia and its role in cancer

Malassezia belongs to the fungal division Basidiomycota and plays an important role in the mycobiome of the mammalian system. The fungus propagates by budding and mostly remains commensal with the host comprising of warm-blooded animals. During infection, it converts from yeast to its pathogenic hyphal form and this leads to many diseases in humans. Currently, there are 18 known species of Malassezia out of which 11 species are related to humans and the prevalence of the species varies with geographical location. In addition to several diseases it causes, recent research shows the direct role of the fungus in promoting oncogenesis. The fungus thrives with a fine balance between commensalism and its pathogenic state. Its high lipid content in the cell wall provides a robust defense system against the host immunogenic factors. In this review, we discuss the role of the fungus and its host cell receptors in promoting inflammation and disease. We highlight the potential procancerous role of the metabolites produced by Malassezia in tumor development and highlight how the antimicrobial peptides like Defensin and Nanovesicles like MalaEx modulate the host defense system. Finally, we discuss the importance of fungal dysbiosis caused by Malassezia and its role in human diseases. Though working with the fungus is difficult for several reasons, utilizing modern genomic approaches to understanding the biology of this fungus is of tremendous clinical importance. This review highlights different ways by which the fungus affects human health and often leads to several life-threatening diseases including cancer.     

Dissecting the fungal biology of Bipolaris papendorfii: from phylogenetic to comparative genomic analysis

Bipolaris papendorfii has been reported as a fungal plant pathogen that rarely causes opportunistic infection in humans. Secondary metabolites isolated from this fungus possess medicinal and anticancer properties. However, its genetic fundamental and basic biology are largely unknown. In this study, we report the first draft genome sequence of B. papendorfii UM 226 isolated from the skin scraping of a patient. The assembled 33.4 Mb genome encodes 11,015 putative coding DNA sequences, of which, 2.49% are predicted transposable elements. Multilocus phylogenetic and phylogenomic analyses showed B. papendorfii UM 226 clustering with Curvularia species, apart from other plant pathogenic Bipolaris species. Its genomic features suggest that it is a heterothallic fungus with a putative unique gene encoding the LysM-containing protein which might be involved in fungal virulence on host plants, as well as a wide array of enzymes involved in carbohydrate metabolism, degradation of polysaccharides and lignin in the plant cell wall, secondary metabolite biosynthesis (including dimethylallyl tryptophan synthase, non-ribosomal peptide synthetase, polyketide synthase), the terpenoid pathway and the caffeine metabolism. This first genomic characterization of B. papendorfii provides the basis for further studies on its biology, pathogenicity and medicinal potential.     

Frequency and aetiology of dermatophytosis in children age 12 and under in the state of Amazonas,Brazil

BackgroundFew scientific studies have evaluated dermatophytosis among children in the state of Amazonas or in the greater northern region of Brazil.AimsThe aim of this study was to research the frequency and aetiology of dermatophytosis in children age 12 and under, who were seen between March 1996 and November 2005 at the Mycology Laboratory of the National Institute of Amazonian Research.MethodsFor mycological diagnoses, epidermal scales and/or hairs were used. A portion of this material was treated with potassium hydroxide for direct examination, and another portion was cultivated in Mycobiotic Agar for the isolation of dermatophytes.ResultsOf the 590 samples analysed, 210 showed positive diagnoses by direct examination and cultivation. Tinea capitis (153 cases) was the most frequent type of dermatophytosis, and Trichophyton tonsurans (121 cases) was the most frequently isolated fungal agent. Tinea corporis was observed in 48 cases where the most frequently isolated fungal agent was also T. tonsurans (17 cases), and the corporal regions most affected were the face, arms and trunk. The laboratory confirmed tinea pedis in 6 cases, and the principal fungal agents isolated were Trichophyton rubrum (3) and Trichophyton mentagrophytes (3). The presence of tinea cruris was confirmed in 3 cases, and T. rubrum, T. tonsurans and Epidermophyton floccosum were isolated from these cases.ConclusionsThe children examined were primarily affected by tinea capitis, and the main fungal agent for this dermatophytosis was T. tonsurans.     

Infection of Keratinocytes with Trichophytum rubrum Induces Epidermal Growth Factor-Dependent RNase 7 and Human Beta-Defensin-3 Expression

Human keratinocytes are able to express various antimicrobial peptides (AMP) to protect the skin from exaggerated microbial colonization and infection. Recently, in vitro growth-inhibiting activity of the skin-derived AMP psoriasin, RNase 7 and human beta-defensin (hBD)-2 against dermatophytes such as Trichophyton (T.) rubrum have been reported. To evaluate whether keratinocytes are able to respond to T. rubrum infection by an induced expression of AMP we exposed primary keratinocytes to living conidia of T. rubrum. This led to conidia germination and mycelial growth which was paralleled by a strong gene induction of the skin-derived AMP RNase 7 and hBD-3. Gene expression of the AMP psoriasin (S100A7) and hBD-2 were only slightly induced. The T. rubrum-mediated RNase 7 gene induction was accompanied by increased secretion of RNase 7. Parallel treatment of the keratinocytes with T. rubrum and the cytokine combination IL-17A/IFN-γ resulted in synergistic induction of RNase 7 and hBD-3 expression. Since patients receiving therapy by inhibition of the epidermal growth factor receptor (EGFR) more often suffer from dermatophytoses we investigated whether EGFR may be involved in the T. rubrum-mediated RNase 7 and hBD-3 induction. Primary keratinocytes incubated with an EGFR blocking antibody as well as with the EGFR antagonist AG1478 showed a significantly diminished RNase 7 and hBD-3 induction upon exposure of the keratinocytes to T. rubrum indicating that EGFR is involved in the T. rubrum-mediated induction of RNase 7 and hBD-3. The growth of T. rubrum in vitro was inhibited by hBD-3 in a dose-dependent manner suggesting that hBD-3 may contribute to cutaneous innate defense against T. rubrum. Taken together our data indicate that keratinocytes are able to initiate a fast defense response towards T. rubrum by the increased expression of AMP active against T. rubrum. A dysregulation of AMP may contribute to chronic and recurring dermatophytoses.     

Boric Acid Inhibition of <Emphasis Type="Italic">Trichophyton rubrum</Emphasis> Growth and Conidia Formation

Trichophyton rubrum is a common human dermatophyte that is the causative agent of 80–93% of fungal infections of the skin and nails. While dermatophyte infections in healthy people are easily treatable with over-the-counter medications, such infections pose a higher risk for patients with compromised immune function and impaired regenerative potential. The efficacy of boric acid (BA) for the treatment of vaginal yeast infections prompted an investigation of the effect of BA on growth and morphology of T. rubrum. This is of particular interest since BA facilitates wound healing, raising the possibility that treating athlete’s foot with BA, either alone or in combination with other antifungal drugs, would combine the benefits of antimicrobial activity and tissue regeneration to accelerate healing of infected skin. The data presented here show that BA represses T. rubrum growth at a concentration reported to be beneficial for host tissue regeneration. Oxygen exposure increases BA toxicity, and mycelia growing under BA stress avoid colonizing the surface of the growth surface, which leads to a suppression of aerial mycelium growth and surface conidia formation. BA penetrates into solid agar matrices, but the relative lack of oxygen below the substrate surface limits the effectiveness of BA in suppressing growth of embedded T. rubrum cells.     

Extensive Deep Dermatophytosis Cause by Trichophyton rubrum in a Patient with Liver Cirrhosis and Chronic Renal Failure

Dermatophytes are the main pathogen of superficial skin fungal infections. On rare occasions, they can cause deep and extensive infections, especially in immunocompromised hosts. We reported a 48-year-old patient with liver cirrhosis and chronic renal failure who developed an extensive deep dermatophytosis with possible hematogenous dissemination. Skin histopathology showed extensive involvement of hair follicles and dermis by fungal elements. The pathogen was cultured from both skin biopsy specimen and central venous line. It was identified as Trichophyton rubrum by morphology and further conformed by sequencing of internal transcribed spacers of ribosomal DNA. The patient died quickly before the identification was available.