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The C-type lectin receptor MelLec recognizes DHN-melanin in conidial spores of Aspergillus fumigatus and other DHN-melanized fungi, revealing an important role for this receptor in antifungal immunity in both mice and humans. Cell receptor triggers antifungal immunity Defence against fungal pathogens in mammals relies on pattern recognition receptors, which are often activated by pathogen virulence factors. One such factor is melanin, a component of the fungal cell wall. Gordon Brown and colleagues identify the melanin-sensing C-type lectin receptor (MelLec) as an endothelial cell receptor for fungal melanin. Activation of this receptor triggers a protective inflammatory response against infection by Aspergillus fungi in mice and humans. MelLec thereby has an important role in host defence against disseminated Aspergillosis . Resistance to infection is critically dependent on the ability of pattern recognition receptors to recognize microbial invasion and induce protective immune responses. One such family of receptors are the C-type lectins, which are central to antifungal immunity 1 . These receptors activate key effector mechanisms upon recognition of conserved fungal cell-wall carbohydrates. However, several other immunologically active fungal ligands have been described; these include melanin 2 , 3 , for which the mechanism of recognition is hitherto undefined. Here we identify a C-type lectin receptor, melanin-sensing C-type lectin receptor (MelLec), that has an essential role in antifungal immunity through recognition of the naphthalene-diol unit of 1,8-dihydroxynaphthalene (DHN)-melanin. MelLec recognizes melanin in conidial spores of Aspergillus fumigatus as well as in other DHN-melanized fungi. MelLec is ubiquitously expressed by CD31 + endothelial cells in mice, and is also expressed by a sub-population of these cells that co-express epithelial cell adhesion molecule and are detected only in the lung and the liver. In mouse models, MelLec was required for protection against disseminated infection with A. fumigatus . In humans, MelLec is also expressed by myeloid cells, and we identified a single nucleotide polymorphism of this receptor that negatively affected myeloid inflammatory responses and significantly increased the susceptibility of stem-cell transplant recipients to disseminated Aspergillus infections. MelLec therefore recognizes an immunologically active component commonly found on fungi and has an essential role in protective antifungal immunity in both mice and humans.

There are few studies on the role of innate immune response in dermatophytosis. An investigation was conducted to define the involvement of Toll-Like Receptors (TLRs) 2 and 4 in localized (LD) and disseminated (DD) dermatophytosis due to T. rubrum. Fifteen newly diagnosed patients, eight patients with LD and seven with DD, defined by involvement of at least three body segments were used in this study. Controls comprised twenty skin samples from healthy individuals undergoing plastic surgery. TLR2 and TLR4 were quantified in skin lesions by immunohistochemistry. A reduced expression of TLR4 in the lower and upper epidermis of both LD and DD patients was found compared to controls; TLR2 expression was preserved in the upper and lower epidermis of all three groups. As TLR4 signaling induces the production of inflammatory cytokines and neutrophils recruitment, its reduced expression likely contributed to the lack of resolution of the infection and the consequent chronic nature of the dermatophytosis. As TLR2 expression acts to limit the inflammatory process and preserves the epidermal structure, its preserved expression may also contribute to the persistent infection and limited inflammation that are characteristic of dermatophytic infections. A literatura sobre o papel da resposta imune inata em dermatofitose é escassa. Este estudo se propôs a investigar a participação dos receptores do tipo Toll 2 e 4 (TLRs) 2 e 4 em pacientes com dermatofitose localizada (LD) e disseminada (DD, definida como lesões em pelo menos três segmentos corpóreos distintos), causadas por Trichophyton rubrum. Foram analisados cortes histológicos de 15 pacientes recém-diagnosticados, oito com LD e sete com DD. O grupo controle foi composto por 20 amostras de pele de indivíduos saudáveis submetidos a cirurgia plástica. TLR-2 e TLR-4 foram quantificados em lesões cutâneas por imunohistoquímica. Encontramos uma expressão reduzida de TLR-4 na epiderme superior e inferior nos dois grupos, LD e DD, quando comparados com o grupo controle; a expressão de TLR-2 foi preservada na epiderme superior e inferior de todos os três grupos. Como a sinalização por TLR-4 induz produção de citocinas inflamatórias e recrutamento de neutrófilos, a menor expressão desta molécula provavelmente contribui para a não resolução da infecção e conseqüente natureza persistente da dermatofitose. Como a sinalização via TLR-2 tem sido descrita como fator de regulação do processo inflamatório e de preservação da estrutura epidérmica, a sua expressão inalterada nas lesões dos pacientes com DD e DL pode contribuir também para a persistência da infecção e do reduzido processo inflamatório que são característicos das infecções por dermatófitos.

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.

Neutrophils are the first leukocytes recruited to the site of infection and are thought to be responsible for fungal elimination from the skin such as dermatophytes. Neutrophils are able to secrete reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) that can kill different fungi, including Aspergillus, spp., Candida albicans, and Phialophora verrucosa. However, NET production in response to Trichophyton rubrum, the main etiologic agent of dermatophytosis, has yet to be studied. We demonstrated that human neutrophils produce NETs against different morphotypes of T. rubrum in a dose-dependent manner and NET formation is dependent on ROS production. In addition, ROS production by human neutrophils in response to T. rubrum is dependent on NADPH oxidase, but not on fungal viability. NETs mediated killing of T. rubrum. Collectively, these results demonstrate that T. rubrum was able to trigger the production of NETs, suggesting that these extracellular structures may represent an important innate immune effector mechanism controlling physiological response to T. rubrum infection.

Chromoblastomycosis is a subcutaneous mycosis that remains a therapeutic challenge, with no standard treatment and high rates of relapse. On the basis of our recent discoveries in mouse models, we tested the efficacy of topial applications of imiquimod to treat patients afflicted with this chronic fungal infection. We report results of treatment for the first 4 recipients of topical imiquimod, all of whom displayed a marked improvement of their lesions, both with and without concurrent oral antifungal therapy.

Abstract The skin is the largest organ in the body and is the site for a diverse set of diseases. Yet, given the complexity of the cutaneous tissue, there is a limited availability of data in the literature on skin proteomics. Here, we proposed an adapted and optimized protocol for the extraction of proteins from human skin, using a combination of chemical and mechanical lysis approaches. For this, we used of a lysis buffer containing 2% SDS, 50 mM TEAB, and a 1% protease and phosphatase inhibitor cocktail, in addition to Matrix A beads and a FastPrep-24 5G homogenizer. For the characterization of the samples, the obtained proteins were purified and digested using the SP3 method (Single-pot, solid phase, sample preparation), and analyzed by nano liquid chromatography coupled with tandem mass spectrometry. In this way, we were able to identify around 6000 proteins in the skin samples from healthy individuals and patients with the fungal infection sporotrichosis. Our improved methodology could significantly enrich our understanding of skin biology and provide new perspectives for the discovery of biomarkers and therapeutic targets for cutaneous diseases.

American cutaneous leishmaniasis (ACL) is a chronic infectious disease caused by different protozoan species of Leishmania, and it is endemic in both tropical and subtropical countries. Using immunohistochemistry, we investigate the density of CD68+, lysozyme+, CD1a+, factor XIIIa+, CD4+, CD8+, CD56+, interferon (IFN)-γ+, and inducible NO synthase (iNOS+) cells. These cells were analyzed from 22 biopsy samples obtained from the lesions of ACL patients, whose infection was caused by Leishmania (Viannia) spp. Histopathological analysis showed dense mononuclear inflammatory infiltration in the dermis, which was composed of lymphocytes, macrophages, plasma cells, and discrete tissue parasitism. Granulomatous reactions were also present in the majority of cases. The density of the activated macrophages was higher than that of inactivated macrophages in the lesions. The density of Langerhans cells (CD1a+) was lower than that of dermal dendrocytes (factor XIIIa+). The density of CD8+ T lymphocytes was higher than that of CD4+ T lymphocytes. The cellular density of these immunological markers in relation to the species of Leishmania demonstrated that L. (Viannia) sp. lesions had higher IFN-γ expression than that Leishmania (Viania) braziliensis lesions. The evaluation of these markers, according to disease progression, did not reveal any significant differences. L. (Viannia) sp. infection leads to a favorable immune response in the host, as predominantly represented by lysozyme+, factor XIIIa+, CD8+ T cells, and the expression of (IFN)-γ+ at the lesion site.

DC. (Asteraceae), a medicinal plant known as \"quitoco,\" \"caculucage,\" \"tabacarana\" and \"madre-cravo,\" is indicated for inflammatory conditions such as bronchitis, arthritis, and inflammation in the uterus and digestive system. This study evaluated the analgesic and anti-inflammatory activities of the triterpenes compounds obtained from aerial parts. The triterpenes compounds β-amyrin, taraxasterol and pseudo-taraxasterol in a mixture (T); β-amyrin, taraxasterol and pseudo-taraxasterol acetates in a mixture (Ta); β-amyrin, taraxasterol, pseudo-taraxasterol acetates in a mixture with β-amyrin, taraxasterol and pseudo-taraxasterol myristates (Tafe) were analyzed in the models of nociception and inflammation. The evaluation of antinociceptive activity was carried out by the acetic acid-induced writhing and tail-flick tests while leukocyte migration to the peritoneal cavity was used for anti-inflammatory profile. The oral administration of T or Tafe (40 mg/kg and 70 mg/kg) and Ta (70 mg/kg) to mice reduced acetic acid-induced writhing. The tail-flick response of mice was not affected by T or Tafe (40 mg/kg). T or Tafe (40 mg/kg) and Ta (70 mg/kg) also inhibited peritoneal leukocyte infiltration following the injection of carrageenan. The results demonstrate the anti-inflammatory and peripheral antinociceptive activity of the triterpenes β-amyrin, taraxasterol, and pseudo-taraxasterol that were decreased when these were acetylated; while the acetylated triterpenes in mixture with myristyloxy triterpenes improved this activity. These compounds seem, at least in part, to be related to the plant's reported activity. The mixtures of hydroxylated, acetylated, and myristate triterpenes isolated from hexanic extracts of DC. were analyzed in the models of nociception and inflammation in mice. The results demonstrate the anti-inflammatory and peripheral antinociceptive activity of the triterpenes β-amyrin, taraxasterol, and pseudo-taraxasterol. This study showed too that the activity of triterpenes may be decreased by their being acetylated, while the acetylated triterpenes in mixture with myristate triterpenes improved this activity. T: Triterpenes compounds β-amyrin, taraxasterol, and pseudo-taraxasterol in a mixture, Ta: Triterpenes compounds β-amyrin, taraxasterol and pseudo-taraxasterol acetates in a mixture, Tafe: Triterpenes compounds β-amyrin, taraxasterol, pseudo-taraxasterol acetates in a mixture with β-amyrin, taraxasterol and pseudo-taraxasterol myristates, Ctrl: Control, Indo: Indomethacin, Dexa: Dexamethasone, EtOAc: Ethyl acetate, MeOH: Methanol.

Dermatophytosis is a very common superficial mycosis, but there are few studies about the human immune response to dermatophytes. We aim to analyze the in situ expression of TNF-α and IL-10 in human dermatophytosis. Expression of TNF-α and IL-10 were evaluated in skin samples from 10 patients with dermatophytosis and 12 healthy subjects using an immunohistochemistry assay. TNF-α and IL-10 were significantly elevated in lesions from patients with dermatophytosis compared to healthy controls. These data illustrate the balance of pro- and anti-inflammatory cytokines suggesting Trichophyton rubrum infection could control the local immune response.

Coccidioidomycosis is an emerging fungal disease in Brazil; adequate maintenance and authentication of Coccidioides isolates are essential for research into genetic diversity of the environmental organisms, as well as for understanding the human disease. Seventeen Coccidioides isolates maintained under mineral oil since 1975 in the Instituto de Medicina Tropical de São Paulo (IMTSP) culture collection, Brazil, were evaluated with respect to their viability, morphological characteristics and genetic features in order to authenticate these fungal cultures. Only five isolates were viable after almost 30 years, showing typical morphological characteristics, and sequencing analysis using Coi-F and Coi-R primers revealed 99% identity with Coccidioides genera. These five isolates were then preserved in liquid nitrogen and sterile water, and remained viable after two years of storage under these conditions, maintaining the same features. Coccidioidomicose é uma doença emergente no Brasil; a manutenção adequada e autenticação de isolados de Coccidioides spp são essenciais para a pesquisa em diversidade genética de micro-organismos, bem como para a compreensão da doença em humanos. Dezessete isolados de Coccidioides preservados em óleo mineral desde 1975 na coleção de culturas do Instituto de Medicina Tropical de São Paulo (IMTSP) foram avaliados com relação à viabilidade, características morfológicas e genéticas, com o objetivo de autenticação das culturas fúngicas. Dos 17 isolados, apenas cinco foram viáveis após quase 30 anos mantidos em óleo mineral, apresentando características morfológicas e moleculares típicas do gênero, o sequenciamento utilizando os oligonucleotídeos Coi-F e Coi-R revelou identidade de 99% com isolados de Coccidioides. Estes cinco isolados foram preservados em nitrogênio líquido e água destilada esterilizada, e permaneceram viáveis após dois anos de armazenamento sob estas condições, mantendo as mesmas características.