The Role of IL-17-Producing Cells in Cutaneous Fungal Infections.

The skin is the outermost layer of the body and is exposed to many environmental stimuli, which cause various inflammatory immune responses in the skin. Among them, fungi are common microorganisms that colonize the skin and cause cutaneous fungal diseases such as candidiasis and dermatophytosis. The skin exerts inflammatory responses to eliminate these fungi through the cooperation of skin-component immune cells. IL-17 producing cells are representative immune cells that play a vital role in anti-fungal action in the skin by producing antimicrobial peptides and facilitating neutrophil infiltration. However, the actual impact of IL-17-producing cells in cutaneous fungal infections remains unclear. In this review, we focused on the role of IL-17-producing cells in a series of cutaneous fungal infections, the characteristics of skin infectious fungi, and the recognition of cell components that drive cutaneous immune cells.

Immunological response and clinical profile in patients with recurrent dermatophytosis.

BACKGROUND: An alarming increase in the number of patients with chronic and recurrent dermatophytosis has invoked the need to study the immunological parameters of the host. OBJECTIVES: To evaluate delayed type of hypersensitivity (DTH) response and immediate hypersensitivity (IH) response by flow cytometry evaluation of immune cells from peripheral blood and intradermal trichophyton skin test in patients with recurrent dermatophytosis. METHODS: A hundred patients with recurrent dermatophytosis and 50 controls (healthy controls and acute dermatophytosis controls) were included. Relevant risk factors for recurrence were analysed, and serum IgE levels were estimated. Flow cytometry evaluation of immune cells in peripheral blood and intradermal trichophyton skin test was done. Dermatophyte pathogens were isolated, and antifungal susceptibility was performed. RESULTS: Trichophyton mentagrophytes complex (95.84%) and T. rubrum (4.16%) were isolated in culture. Serum IgE was elevated in 83.15% cases (p = .01). IFN-γ+ cells (p = .0501, p = .0001, p = .0014), Th1 cells (p = .1197, p = .0024, p = .0169), IL-17+ cells (p = .0127, p = .0006, p = .0007) and Th17 cells (p = .0634, p = .0001, p = .0054) were reduced, and IL-4+ cells (p = .0108, p = .0175, p = .0018) were increased in cases. Intradermal test demonstrated negative DTH response in all cases (p < .001, p < .001, p < .001), strongly positive IH response in 6%, and borderline positive IH response in 85% cases (p = .018, p < .001, p < .001). Topical corticosteroids application, undergarment types (tight fit), poor frequency of washing clothes, family history of tinea, sharing of towels were significant risk factors for recurrent dermatophytosis. CONCLUSIONS: Reduced IFN-γ+ , Th1, IL-17+ and Th17 cells population along with impaired DTH response by the intradermal test was observed in patients with recurrent dermatophytosis.

Skin Immunity to Dermatophytes: From Experimental Infection Models to Human Disease.

Dermatophytoses (ringworms) are among the most frequent skin infections and are a highly prevalent cause of human disease worldwide. Despite the incidence of these superficial mycoses in healthy people and the compelling evidence on chronic and deep infections in immunocompromised individuals, the mechanisms controlling dermatophyte invasion in the skin are scarcely known. In the last years, the association between certain primary immunodeficiencies and the susceptibility to severe dermatophytosis as well as the evidence provided by novel experimental models mimicking human disease have significantly contributed to deciphering the basic immunological mechanisms against dermatophytes. In this review, we outline the current knowledge on fungal virulence factors involved in the pathogenesis of dermatophytoses and recent evidence from human infections and experimental models that shed light on the cells and molecules involved in the antifungal cutaneous immune response. The latest highlights emphasize the contribution of C-type lectin receptors signaling and the cellular immune response mediated by IL-17 and IFN-γ in the anti-dermatophytic defense and skin inflammation control.

In situ immune response in human dermatophytosis: possible role of Langerhans cells (CD1a+) as a risk factor for dermatophyte infection.

Dermatophytosis is a cutaneous mycosis caused by a plethora of keratinophilic fungi, but Trichophyton rubrum is the most common etiological agent. Despite its high prevalence worldwide, little is known about the host defense mechanisms in this infection, particularly the in situ immune response. Using an immunohistochemistry approach, we investigated the density of CD1a+, factor XIIIa+ and CD68+ cells in the skin of dermatophytosis patients. Langerhans cells (CD1a+ cells) were significantly decreased in the epidermis of patients, both in affected and unaffected areas. In the dermis, however, no differences in the density of macrophages (CD68+ cells) and dermal dendrocytes (factor XIIIa+ cells) were observed. These results suggest that the decreased number of Langerhans cells may be a risk factor for development of dermatophytosis.

A Mouse Model of Trichophyton Inflammation Based on Trichophytin-induced Contact Hypersensitivity.

The prevalence of Trichophyton-induced superficial skin mycosis is very high among human patients. Dermatophytes generally infect the epidermis, especially the stratum corneum, forming scales, hyperkeratosis, and vesicles. The important roles played by the immune system in Trichophyton infection are detection of fungal invasion and elimination of fungi.These immune mechanisms are presumed to involve not only innate immunity but also acquired immunity. Therefore, there is a substantial need for studies on treatment methods based on new basic knowledge, and the elucidation of immunological mechanisms of Trichophyton-induced inflammatory reactions is especially important.However, since Trichophyton cannot colonize on the mouse skin, we tried to develop a model for Trichophyton inflammation induced by trichophytin extracted from Trichophyton mentagrophytes using a method based on contact hypersensitivity.Trichophytin is a crude extract that mainly contains fungal cell wall constituents including ß-glucan and zymosan. In this model, TLR2, TLR4, and dectin-1 were highly expressed, and production of IL-17A and IL23 was observed. This indicates that we succeeded in inducing fungal-specific inflammation in the mice.In this review, we introduce a mouse Trichophyton inflammation model developed to investigate the immunological mechanisms of Trichophyton-induced inflammatory reactions. In addition, we report results of evaluation of anti-inflammatory and anti-itching effects of anti-fungal agents using the inflammation model.

Multiple abscesses in the lower extremities caused by Trichophyton rubrum.

BACKGROUND: Dermatophytes are keratinophilic fungi, that usually infect the hair, stratum corneum, and nails. However, dermatophytes occasionally invade the dermis, subcutaneous tissues, and internal organs, resulting in a condition called deep dermatophytosis. We report a case of an unusual presentation of Trichophyton rubrum infection causing multiple fungal abscesses in the lower extremities of an immunocompromised patient. CASE PRESENTATION: A 66-year-old male who had been receiving immunosuppressive drugs for 7 years developed numerous subcutaneous nodules in the lower extremities. The yellow purulent fluid obtained from the cyst was positive for T. rubrum. Topical bifonazole cream was effective for tinea pedis, but oral Sporanox 400 mg/day was discontinued after 2 months because the patient died from pneumonia after hospitalization for a lumbar fracture. CONCLUSIONS: Although deep dermatophytosis is very rare, dermatomycosis should be considered in any examination of patients who are receiving immunosuppressive drugs. Fungi can enter the bloodstream and disseminate to distant major organs, including the lymph nodes, liver, brain, and bone, which often causes systemic infections that can be fatal.

Th1 and Th17 Immune Responses Act Complementarily to Optimally Control Superficial Dermatophytosis.

Dermatophytoses are among the most common fungal infections worldwide, but little is known about the immune response in them. By comparing Trichophyton benhamiae acute superficial dermatophytosis in wild-type and Rag2-/- mice, we showed that TCR-mediated immunity is critical for fungal clearance and clinical recovery. In WT mice, CD4+ T cells isolated from the skin-draining lymph nodes exhibit both T helper type (Th) 1 and Th17 differentiation during infection, with regard to produced cytokines or mRNA levels of transcription factors. Using IL-17A- and IFN-γ-deficient mice, we showed that IL-17A and IFN-γ are individually dispensable but together contribute to the optimal resolution of dermatophytosis. Furthermore, we generated and infected IL-17A and IFN-γ double-deficient mice and showed that both fungal clearance and clinical recovery were much lower in these mice than in single-deficient mice, suggesting the complementary roles of the two cytokines in dermatophytosis resolution. Thus, our data suggest that TCR-mediated immunity is critical for the optimal control of superficial dermatophytosis and that adaptive immunity is polarized to both Th1 and Th17 responses, with the Th17 antifungal response acting on dermatophyte clearance and the Th1 response being involved in both fungal clearance and Th17-inflammation down-modulation.

Extracellular Vesicles From the Dermatophyte Trichophyton interdigitale Modulate Macrophage and Keratinocyte Functions.

The release of biomolecules critically affects all pathogens and their establishment of diseases. For the export of several biomolecules in diverse species, the use of extracellular vesicles (EVs) is considered to represent an alternative transport mechanism, but no study to date has investigated EVs from dermatophytes. Here, we describe biologically active EVs from the dermatophyte Trichophyton interdigitale, a causative agent of mycoses worldwide. EV preparations from T. interdigitale were examined using nanoparticle-tracking analysis, which revealed vesicular structures 20-380 nm in diameter. These vesicles induced the production of proinflammatory mediators by bone marrow-derived macrophages (BMDMs) and keratinocytes in a dose-dependent manner, and an addition of the EVs to BMDMs also stimulated the transcription of the M1-polarization marker iNOS (inducible nitric oxide synthase) and diminished the expression of the M2 markers arginase-1 and Ym-1. The observed M1 macrophages' polarization triggered by EVs was abolished in cells obtained from knockout Toll-like receptor-2 mice. Also, the EVs-induced productions of pro-inflammatory mediators were blocked too. Furthermore, the EVs from T. interdigitale enhanced the fungicidal activity of BMDMs. These results suggest that EVs from T. interdigitale can modulate the innate immune response of the host and influence the interaction between T. interdigitale and host immune cells. Our findings thus open new areas of investigation into the host-parasite relationship in dermatophytosis.

Exoproteome Analysis of Human Pathogenic Dermatophyte Species and Identification of Immunoreactive Proteins.

PURPOSE: Increasing incidence of onychomycosis and tinea pedis in humans of industrialized countries together with deep tissue infections are a therapeutic challenge in clinical mycology. For a better understanding of the pathology and immunology of infection, the authors analyze the exoproteomes of three reference strains of the most common clinical dermatophyte species (Trichophyton rubrum, Trichophyton interdigitale, Arthroderma benhamiae) and of Trichophyton strains isolated from affected patients. EXPERIMENTAL DESIGN: Extracellular proteins of those in vitro grown strains are separated via 2D High Performance Electrophoresis and identified by mass spectrometry to find proteins with provoked host immune reactivity. RESULTS: More than 80 secreted proteins including virulence factors such as peptidases and other hydrolases are identified. By Western blotting with respective patient sera, up to 31 proteins with significant antigen-antibody reactions are detected in comparison with control sera, for example, peptidases as well as several oxidoreductases. One protein, beta-glucosidase F2SZI9 seems to be a commonly processed antigen in all Trichophyton infections. CONCLUSIONS AND CLINICAL RELEVANCE: These first global exoproteome data of three dermatophyte species can be a stepping stone on the way to further study the molecular mechanisms of Trichophyton pathogenicity-associated traits. Possible candidates for potential new diagnostic methods or vaccination have to be validated in further investigations.

Diffuse dermatophytosis occurring on dimethyl fumarate therapy.

BACKGROUND: Opportunistic infections have occurred during dimethyl fumarate (DMF) therapy. OBJECTIVE: Diffuse skin dermatophytosis which occurred during DMF therapy in the setting of lymphopenia is described. METHODS AND RESULTS: The clinical course, the lymphocyte subset profile, and dermatologic evaluations were reviewed. In both instances, there was no other cause of lymphopenia or immune suppression, and it is likely that the tinea infections are associated with DMF therapy. CONCLUSION: The occurrence of dermatophytosis widens the spectrum of opportunistic infections associated with DMF therapy. Further research is necessary to fully elucidate the mechanism of lymphopenia and potentially impaired immune competence during DMF therapy.

IL-17-Mediated Immunity Controls Skin Infection and T Helper 1 Response during Experimental Microsporum canis Dermatophytosis.

Despite worldwide prevalence of superficial mycoses, the immune response in dermatophytosis has scarcely been investigated. In this study, we developed a model of superficial skin infection in C57BL/6 mice with Microsporum canis, a highly prevalent human pathogen. This model mimics mild inflammatory human dermatophytosis, characterized by neutrophil recruitment and fungal invasion limited to the epidermis and exhibits the establishment of a specific T helper type 17 immune response during infection. By using IL-17RA- or IL-17A/F-deficient mice we showed that, in the absence of a functional IL-17 pathway, M. canis extensively colonizes the epidermis and promotes an exaggerated skin inflammation and a shift to an IFN-γ-mediated (T helper type 1) response. IL-17 signaling was not involved in neutrophil influx to skin or fungal invasion to deeper tissues. Finally, this study shows that skin langerin-expressing cells contribute to the antifungal T helper type 17 response in vivo. In conclusion, these data directly show a dual function of IL-17 cytokines in dermatophytosis by controlling superficial infection and down-modulating a T helper type 1 antifungal response.

Invasive Trichophyton rubrum mimicking blastomycosis in a patient with solid organ transplant.

We present a case of tissue invasive Trichophyton rubrum (T. rubrum) histologically mimicking blastomycosis in a patient with kidney transplant on chronic immunosuppression. Invasive dermatophyte infections are rare, and present a diagnostic challenge to the dermatopathologist due to atypical clinical and histopathological presentations.

A Unique Clinicopathological Manifestation of Fungal Infection: A Case Series of Deep Dermatophytosis in Immunosuppressed Patients.

BACKGROUND: Dermatophytes are the most common cause of superficial fungal infections in humans. Deep dermatophytosis, however, is rare, described to date only in isolated case reports, usually in the setting of systemic immunosuppression. OBJECTIVE: To present the 15-year experience of a tertiary dermato-mycology clinic with the diagnosis and treatment of deep dermatophytosis. METHODS: Patients were identified by database search. Clinical, mycological, histological, and treatment data were collected from the medical files. RESULTS: Ten patients were identified: nine after solid-organ transplantation and one undergoing chemotherapy, all diagnosed within 3 years after beginning immunosuppression (average 7.5 months). The infective agent in nine cases was Trichophyton rubrum. All patients presented with concurrent superficial fungal infections. Complete resolution was noted in response to systemic antifungal agents. There was no histological evidence of hair-follicle involvement. LIMITATIONS: The limitations of the study were the retrospective design and the small cohort size. CONCLUSION: This case-series study suggests that deep dermatophytosis is a separate entity, distinct from Majocchi's granuloma. It occurs only in immunocompromised patients and is characterized by discrete nodules, an indolent course, the absence of follicular invasion, and proximity to a superficial dermatophyte infection. Systemic antifungal treatment leads to complete resolution. The urgent need for the treatment of superficial fungal infections in immunocompromised patients is emphasized.

Cellular immunodeficiency related to chronic dermatophytosis in a patient with Schistosoma mansoni infection: can schistosomiasis induce immunodeficiency?

Here, we describe a case of hepatosplenic schistosomiasis that progressed to widespread persistent dermatophytosis. Significant T and B lymphocytopenia was confirmed. T-cell deficit is associated with increased susceptibility to fungal infections of skin and mucous membranes. The accumulation of a large amount of blood cells in the spleen could have played a crucial role in the development of lymphocytopenia in the present case. Alternatively, the schistosomiasis-induced increase in prostaglandin E2 levels could have inhibited the production of interferon-γ, a cytokine fundamental to fungal resistance. This case shows the potential of hepatosplenic schistosomiasis to impair the immune response.

TLR2-/- Mice Display Increased Clearance of Dermatophyte Trichophyton mentagrophytes in the Setting of Hyperglycemia.

Dermatophytosis is one of the most common human infections affecting both immunocompetent individuals and immunocompromised patients, in whom the disease is more aggressive and can reach deep tissues. Over the last decades, cases of deep dermatophytosis have increased and the dermatophyte-host interplay remains poorly investigated. Pattern recognition molecules, such as Toll-like receptors (TLR), play a crucial role against infectious diseases. However, there has been very little research reported on dermatophytosis. In the present study, we investigated the role of TLR2 during the development of experimental deep dermatophytosis in normal mice and mice with alloxan-induced diabetes mellitus, an experimental model of diabetes that exhibits a delay in the clearance of the dermatophyte, Trichophyton mentagrophytes (Tm). Our results demonstrated that inoculation of Tm into the footpads of normal mice increases the expression of TLR2 in CD115+Ly6Chigh blood monocytes and, in hypoinsulinemic-hyperglycemic (HH) mice infected with Tm, the increased expression of TLR2 was exacerbated. To understand the role of TLR2 during the development of murine experimental deep dermatophytosis, we employed TLR2 knockout mice. Tm-infected TLR2-/- and TLR2+/+ wild-type mice exhibited similar control of deep dermatophytic infection and macrophage activity; however, TLR2-/- mice showed a noteworthy increase in production of IFN-γ, IL-10, and IL-17, and an increased percentage of splenic CD25+Foxp3+ Treg cells. Interestingly, TLR2-/- HH-Tm mice exhibited a lower fungal load and superior organization of tissue inflammatory responses, with high levels of production of hydrogen peroxide by macrophages, alongside low TNF-α and IL-10; high production of IL-10 by spleen cells; and increased expansion of Tregs. In conclusion, we demonstrate that TLR2 diminishes the development of adaptive immune responses during experimental deep dermatophytosis and, in a diabetic scenario, acts to intensify a non-protective inflammatory response.