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1.
PLoS Negl Trop Dis ; 15(8): e0009611, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34383752

RESUMO

BACKGROUND: Chromoblastomycosis (CBM), represents one of the primary implantation mycoses caused by melanized fungi widely found in nature. It is characterized as a Neglected Tropical Disease (NTD) and mainly affects populations living in poverty with significant morbidity, including stigma and discrimination. METHODS AND FINDINGS: In order to estimate the global burden of CBM, we retrospectively reviewed the published literature from 1914 to 2020. Over the 106-year period, a total of 7,740 patients with CBM were identified on all continents except Antarctica. Most of the cases were reported from South America (2,619 cases), followed by Africa (1,875 cases), Central America and Mexico (1,628 cases), Asia (1,390 cases), Oceania (168 cases), Europe (35 cases), and USA and Canada (25 cases). We described 4,022 (81.7%) male and 896 (18.3%) female patients, with the median age of 52.5 years. The average time between the onset of the first lesion and CBM diagnosis was 9.2 years (range between 1 month to 50 years). The main sites involved were the lower limbs (56.7%), followed by the upper limbs (19.9%), head and neck (2.9%), and trunk (2.4%). Itching and pain were reported by 21.5% and 11%, respectively. Malignant transformation was described in 22 cases. A total of 3,817 fungal isolates were cultured, being 3,089 (80.9%) Fonsecaea spp., 552 (14.5%) Cladophialophora spp., and 56 Phialophora spp. (1.5%). CONCLUSIONS AND SIGNIFICANCE: This review represents our current knowledge on the burden of CBM world-wide. The global incidence remains unclear and local epidemiological studies are required to improve these data, especially in Africa, Asia, and Latin America. The recognition of CBM as NTD emphasizes the need for public health efforts to promote support for all local governments interested in developing specific policies and actions for preventing, diagnosing and assisting patients.


Assuntos
Cromoblastomicose/epidemiologia , Carga Global da Doença , Ascomicetos/isolamento & purificação , Fonsecaea/isolamento & purificação , Humanos , Phialophora/isolamento & purificação
2.
J Mycol Med ; 31(2): 101114, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33684836

RESUMO

Chromoblastomycosis is a chronic subcutaneous fungal infection caused by melanized fungi. It is usually an occupational mycosis affecting people in rural areas in tropical and subtropical regions. We present two cases of chromoblastomycosis in Mexican farmers, characterized by skin verrucous plaques. Direct examination with KOH 10% showed the presence of muriform cells. The fungal isolation was carried out in Sabouraud dextrose agar and molecular identification was achieved by 18S-ITS1-5.8S-ITS2-28S rRNA gene amplification and sequencing. Fonsecaeamonophora was identified in both cases. A therapy with itraconazole and terbinafine was used with a partial favorable response. However, patients did not return for medical examination after 4 months. The current status of the patients is unknown. We reported the first two cases of chromoblastomycosis caused by F. monophora in Mexico.


Assuntos
Antifúngicos/farmacologia , Cromoblastomicose/diagnóstico , Fonsecaea/efeitos dos fármacos , Fonsecaea/genética , Pele/microbiologia , Adulto , Idoso , Antifúngicos/uso terapêutico , Cromoblastomicose/tratamento farmacológico , DNA Fúngico/genética , DNA Espaçador Ribossômico/genética , Fazendeiros , Fonsecaea/classificação , Fonsecaea/patogenicidade , Humanos , Masculino , México , Testes de Sensibilidade Microbiana , Análise de Sequência de DNA , Pele/patologia
3.
Microbiol Res ; 244: 126668, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33359842

RESUMO

Fonsecaea monophora, which is very similar to Fonsecaea pedrosoi in morphological features, has been commonly misdiagnosed as F. pedrosoi. Like F. pedrosoi, F. monophora has been also identified as a predominant pathogen of Chromoblastomycosis (CBM). Melanin has been recognized as a virulence factor in several fungi, however, it is still largely unknown about the biological role of melanin and how melanin is synthesized in F. monophora. In this study, we identified two putative polyketide synthase genes (pks), AYO21_03016 (pksA) and AYO21_10638, by searching against the genome of F. monophora. AYO21_03016 and AYO21_10638 were further targeted disrupted by Agrobacterium tumefaciens-mediated transformation (ATMT). We discovered that pksA gene was the major polyketide synthase required for melanin synthesis in F. monophora, rather than AYO21_10638. Phenotypic analysis showed that, knocking out of the pksA gene attenuated melanogenesis, growth rate, sporulation ability and virulence of F. monophora, as compared with wild-type and complementation strain (pksA-C). Furthermore, the ΔpksA mutant was confirmed to be more sensitive to the oxidative stress, extreme pH environment, and antifungal drugs including itraconazole (ITC), terbinafine (TER), and amphotericin B (AMB). Taken together, these findings enabled us to comprehend the role of pksA in regulating DHN-melanin pathway and its effect on the biological function of F. monophora.


Assuntos
Proteínas de Bactérias/genética , Cromoblastomicose/microbiologia , Fonsecaea/efeitos dos fármacos , Fonsecaea/enzimologia , Melaninas/biossíntese , Policetídeo Sintases/genética , Esporos Fúngicos/crescimento & desenvolvimento , Anfotericina B/farmacologia , Antifúngicos/farmacologia , Proteínas de Bactérias/metabolismo , Fonsecaea/genética , Fonsecaea/crescimento & desenvolvimento , Deleção de Genes , Genoma Fúngico , Humanos , Itraconazol/farmacologia , Policetídeo Sintases/metabolismo , Esporos Fúngicos/efeitos dos fármacos , Esporos Fúngicos/genética , Esporos Fúngicos/metabolismo , Terbinafina/farmacologia
4.
PLoS One ; 15(12): e0243231, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33264365

RESUMO

Fonsecaea pedrosoi is one of the main agents of chromoblastomycosis, a chronic subcutaneous mycosis. Itraconazole (ITC) is the most used antifungal in its treatment, however, in vitro antifungal susceptibility tests are important to define the best therapy. These tests are standardized by the Clinical and Laboratory Standards Institute (CLSI), but these protocols have limitations such as the high complexity, cost and time to conduct. An alternative to in vitro susceptibility test, which overcomes these limitations, is FTIR. This study determined the minimum inhibitory concentration (MIC) of itraconazole for F. pedrosoi, using FTIR and chemometrics. The susceptibility to ITC of 36 strains of F. pedrosoi was determined according to CLSI and with the addition of tricyclazole (TCZ), to inhibit 1,8-dihydroxynaphthalene (DHN)-melanin biosynthesis. Strains were grown in Sabouraud agar and prepared for Attenuated Total Reflection (ATR)/FTIR. Partial least squares (PLS) regression was performed using leave-one-out cross-validation (by steps of quintuplicates), then tested on an external validation set. A coefficient of determination (R²) higher than 0.99 was obtained for both the MIC-ITC and MIC-ITC+TCZ ATR/PLS models, confirming a high correlation of the reference values with the ones predicted using the FTIR spectra. This is the first study to propose the use of FTIR and chemometric analyses according to the M38-A2 CLSI protocol to predict ITC MICs of F. pedrosoi. Considering the limitations of the conventional methods to test in vitro susceptibility, this is a promising methodology to be used for other microorganisms and drugs.


Assuntos
Antifúngicos/farmacologia , Fonsecaea/efeitos dos fármacos , Itraconazol/farmacologia , Cromoblastomicose/tratamento farmacológico , Cromoblastomicose/microbiologia , Fonsecaea/química , Humanos , Análise dos Mínimos Quadrados , Testes de Sensibilidade Microbiana/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos
5.
Front Immunol ; 11: 540064, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193308

RESUMO

Chromoblastomycosis is a chronic and progressive subcutaneous mycosis caused mainly by the fungus Fonsecaea pedrosoi. The infection is characterized by erythematous papules and histological sections demonstrating an external layer of fibrous tissue and an internal layer of thick granulomatous inflammatory tissue containing mainly macrophages and neutrophils. Several groups are studying the roles of the innate and adaptive immune systems in F. pedrosoi infection; however, few studies have focused on the role of neutrophils in this infection. In the current study, we verify the importance of murine neutrophils in the killing of F. pedrosoi conidia and hyphae. We demonstrate that phagocytosis and reactive oxygen species during infection with conidia are TLR-2- and TLR-4-dependent and are essential for conidial killing. Meanwhile, hyphal killing occurs by NET formation in a TLR-2-, TLR-4-, and ROS-independent manner. In vivo experiments show that TLR-2 and TLR-4 are also important in chromoblastomycosis infection. TLR-2KO and TLR-4KO animals had lower levels of CCL3 and CXCL1 chemokines and impaired neutrophil migration to the infected site. These animals also had higher fungal loads during infection with F. pedrosoi conidia, confirming that TLR-2 and TLR-4 are essential receptors for F. pedrosoi recognition and immune system activation. Therefore, this study demonstrates for the first time that neutrophil activation during F. pedrosoi is conidial or hyphal-specific with TLR-2 and TLR-4 being essential during conidial infection but unnecessary for hyphal killing by neutrophils.


Assuntos
Cromoblastomicose/imunologia , Fonsecaea/imunologia , Hifas/imunologia , Neutrófilos/imunologia , Esporos Fúngicos/imunologia , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Quimiocina CCL3/genética , Quimiocina CCL3/imunologia , Quimiocina CXCL1/genética , Quimiocina CXCL1/imunologia , Cromoblastomicose/genética , Cromoblastomicose/patologia , Camundongos , Camundongos Knockout , Neutrófilos/patologia , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética
6.
Lett Appl Microbiol ; 71(5): 490-497, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32777092

RESUMO

The aim of this study was to synthesize and investigate the in vitro antifungal properties of 23 cinnamyl Schiff bases. In addition, cytotoxic effects of such cinnamyl Schiff bases against human lung, kidney or red blood cells were also checked. The compounds were synthesized in a single-step, 2 min of reaction under microwave irradiation produced up to 97% yield. Six of the 23 cinnamyl Schiff bases possessed antifungal activities against strains of Candida, Aspergillus, Fonsecaea and, particularly, Cryptococcus species. Indeed, cinnamyl Schiff bases 1 and 23 exhibited minimum inhibitory concentration (MIC) values more than twofold lower than fluconazole (FCZ) against all the Cryptococcus neoformans strains (MIC = 1·33, 1·4 and 5·2 µg ml-1 , respectively) and Cryptococcus gattii strains (MIC = 5·3, 2·8 and 9·2 µg ml-1 , respectively) (12 strains of each species) while cinnamyl Schiff base 11 was as potent as FCZ against all strains from both Cryptococcus species. No significant cytotoxic effects were observed for Schiff bases against human lung, kidney or red blood cells, all presenting selective indexes higher than 10. In conclusion, this study revealed cinnamyl Schiff bases, especially 1 and 23, as new lead anticryptococcal agents for the discovery of novel antifungal drugs. SIGNIFICANCE AND IMPACT OF THE STUDY: The occurrence and severity of fungal infections have increased in recent decades due to resistance to available antifungal drugs and the appearance of new emerging pathogens. Thus, the search for new antifungal agents is mandatory. From a series of 23 cinnamyl Schiff bases, two compounds (1 and 23) were interrogated as new anticryptococcal agents without significant cytotoxicity against human lung, kidney or red blood cells. In turns, these new Schiff bases are lead compounds for the discovery of novel antifungal drugs.


Assuntos
Antifúngicos/farmacologia , Micoses/tratamento farmacológico , Bases de Schiff/farmacologia , Antifúngicos/síntese química , Antineoplásicos/farmacologia , Aspergillus/efeitos dos fármacos , Candida/efeitos dos fármacos , Cryptococcus gattii/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Fluconazol/farmacologia , Fonsecaea/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Bases de Schiff/síntese química
8.
Emerg Infect Dis ; 26(6): 1201-1211, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32441639

RESUMO

Chromoblastomycosis is an implantation fungal infection. Twenty years ago, Madagascar was recognized as the leading focus of this disease. We recruited patients in Madagascar who had chronic subcutaneous lesions suggestive of dermatomycosis during March 2013-June 2017. Chromoblastomycosis was diagnosed in 50 (33.8%) of 148 patients. The highest prevalence was in northeastern (1.47 cases/100,000 persons) and southern (0.8 cases/100,000 persons) Madagascar. Patients with chromoblastomycosis were older (47.9 years) than those without (37.5 years) (p = 0.0005). Chromoblastomycosis was 3 times more likely to consist of leg lesions (p = 0.003). Molecular analysis identified Fonsecaea nubica in 23 cases and Cladophialophora carrionii in 7 cases. Of 27 patients who underwent follow-up testing, none were completely cured. We highlight the persistence of a high level of chromoblastomycosis endemicity, which was even greater at some locations than 20 years ago. We used molecular tools to identify the Fonsecaea sp. strains isolated from patients as F. nubica.


Assuntos
Ascomicetos , Cromoblastomicose , Antifúngicos/uso terapêutico , Ascomicetos/genética , Cromoblastomicose/diagnóstico , Cromoblastomicose/tratamento farmacológico , Cromoblastomicose/epidemiologia , Fonsecaea , Humanos , Madagáscar/epidemiologia
9.
Mycopathologia ; 185(3): 467-476, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32277381

RESUMO

BACKGROUND: Chromoblastomycosis is a chronic, progressive fungal disease of the skin and subcutaneous tissue caused by a unique group of dematiaceous fungi. Fonsecaea monophora, a new species distinct from Fonsecaea pedrosoi strains, is the main pathogen responsible for chromoblastomycosis in south China. Macrophages can be polarized into two categories: classically activated and alternatively activated. OBJECTIVES: Little is known about the relationship between F. monophora and macrophage polarization. This study aimed to study the effect of F. monophora on the polarization of THP-1 cells to macrophages. METHODS: We established coculture systems of F. monophora and THP-1-derived macrophages in different activation states. RESULTS: F. monophora enhanced the phagocytosis by macrophages in the initially activated state and weakened the phagocytosis by classically activated macrophages without affecting that by alternatively activated macrophages. Classically activated macrophages had the strongest killing effect on F. monophora, while the initially activated macrophages had the weakest. The pathogen could not be rapidly cleared by any type of macrophage. F. monophora promoted the expression of proinflammatory cytokines and inhibited that of anti-inflammatory cytokines. CONCLUSIONS: F. monophora promoted the polarization of THP-1 cells to classically activated macrophages and inhibited that of THP-1 cells to alternatively activated macrophages.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Citocinas/metabolismo , Fonsecaea/fisiologia , Macrófagos/microbiologia , Células THP-1/microbiologia , Biomarcadores , Diferenciação Celular , Técnicas de Cocultura , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Polarização de Fluorescência , Fonsecaea/imunologia , Humanos , Macrófagos/imunologia , Fagocitose , Reação em Cadeia da Polimerase em Tempo Real/métodos
10.
Fungal Biol ; 124(3-4): 194-204, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32220380

RESUMO

Chromoblastomycosis is a neglected disease characterized by cutaneous, subcutaneous or disseminated lesions. It is considered an occupational infectious disease that affects mostly rural workers exposed to contaminated soil and vegetal matter. Lesions mostly arise after a traumatic inoculation of herpotrichiellaceous fungi from the Chaetothyriales order. However, the environmental niche of the agents of the disease remains obscure. Its association with insects has been predicted in a few studies. Therefore, the present work aimed to analyze if social insects, specifically ants, bees, and termites, provide a suitable habitat for the fungi concerned. The mineral oil flotation method was used to isolate the microorganisms. Nine isolates were recovered and phylogenetic analysis identified two strains as potential agents of chromoblastomycosis, i.e., Fonsecaea pedrosoi CMRP 3076, obtained from a termite nest (n = 1) and Rhinocladiella similis CMRP 3079 from an ant exoskeleton (n = 1). In addition, we also identified Fonsecaea brasiliensis CMRP 3445 from termites (n = 1), Exophiala xenobiotica CMRP 3077 from ant exoskeleton (n = 1), Cyphellophoraceae CMRP 3103 from bees (n = 1), Cladosporium sp. CMRP 3119 from bees (n = 1), Hawksworthiomyces sp. CMRP 3102 from termites (n = 1), and Cryptendoxyla sp. from termites (n = 2). The environmental isolate of F. pedrosoi CMRP 3076 was tested in two animal models, Tenebrio molitor and Wistar rat, for its pathogenic potential with fungal retention in T. molitor tissue. In the Wistar rat, the cells resembling muriform cells were observed 30 d after inoculation.


Assuntos
Ascomicetos , Cromoblastomicose/microbiologia , Reservatórios de Doenças/microbiologia , Animais , Formigas/microbiologia , Ascomicetos/genética , Ascomicetos/isolamento & purificação , Abelhas/microbiologia , Cladosporium/genética , Cladosporium/isolamento & purificação , Fonsecaea/genética , Fonsecaea/isolamento & purificação , Genes Fúngicos , Humanos , Insetos , Isópteros/microbiologia , Modelos Animais , Patologia Molecular , Filogenia , Ratos , Ratos Wistar/microbiologia , Microbiologia do Solo , Tenebrio/microbiologia
11.
Ann Dermatol Venereol ; 147(5): 377-382, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32220474

RESUMO

INTRODUCTION: Chromoblastomycosis (CBM) is a chronic fungal infection of the skin and subcutaneous tissue caused by dematiaceous fungi. CBM lesions are recalcitrant and extremely difficult to eradicate. We report three cases of CBM with difficulties in therapeutic management. OBSERVATION: Three men aged 36, 50 and 67 years, all farmers, presented for between three and ten years with hyperkeratotic, scaly plaques with black dots on the right thigh and left leg, respectively. For all patients, mycological examination showed fumagoid cells, all of which were pathognomonic for CBM. PCR identified Fonsecaeanubica in one patient and Cladophialophoracarrionii in two patients. All patients received itraconazole 200mg/day for over 18 months. Two patients required combined therapy with terbinafine for seven months, which improved lesions; however, relapse occurred in one patient during the 5th month of this combined therapy and five months after the end of this treatment in the other. The patient on monotherapy (itraconazole) also presented recurrence of lesions five months after the end of treatment. DISCUSSION: Itraconazole is the standard therapy for CBM, with cure rates ranging from 15 to 80%. Success with itraconazole after eight to twelve months was reported by several authors. Fonsecaea and Cladophialophora are the most common species found in Madagascar, and while these organisms are susceptible to triazoles in vitro, clinical response is not so clear-cut. CONCLUSION: Although unavailable in Madagascar, posaconazole and isavoconazole appear to be effective in treating chromoblastomycosis.


Assuntos
Ascomicetos , Cromoblastomicose , Fonsecaea , Adulto , Idoso , Cromoblastomicose/diagnóstico , Cromoblastomicose/tratamento farmacológico , Recursos em Saúde , Humanos , Madagáscar , Masculino , Pessoa de Meia-Idade
12.
Mycopathologia ; 185(2): 245-256, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32008205

RESUMO

The chromoblastomycosis is a subcutaneous mycosis with a high morbidity rate, Fonsecaea pedrosoi being the largest etiologic agent of this mycosis, usually confined to the skin and subcutaneous tissues. Rarely people get the cure, because the therapies shown to be deficient and few studies report the host-parasite relationship. Dendritic cells (DCs) are specialized in presenting antigens to naïve T lymphocytes inducing primary immune responses. Therefore, we propose to study the migratory capacity of DCs after infection with conidia of F. pedrosoi. The phenotype of DCs was evaluated using cells obtained from footpad and lymph nodes of BALB/c mice after 12, 24 and 72 h of infection. After 24 and 72 h of infection, we found a significant decrease in DCs in footpad and a significant increase in the lymph nodes after 72 h. The expression of surface markers and co-stimulatory molecules were reduced in cells obtained from footpad. To better assess the migratory capacity of DCs migration from footpad, CFSE-stained conidia were injected subcutaneously. We found that after 12 and 72 h, CD11c+ cells were increased in regional lymph nodes, leading us to believe that DCs (CD11c+) were able to phagocytic conidia present in footpad and migrated to regional lymph nodes.


Assuntos
Cromoblastomicose/imunologia , Células Dendríticas/metabolismo , Fonsecaea , Linfonodos , Esporos Fúngicos/imunologia , Animais , Ascomicetos/imunologia , Ascomicetos/patogenicidade , Antígeno CD11c/metabolismo , Movimento Celular , Fonsecaea/imunologia , Fonsecaea/patogenicidade , Camundongos , Camundongos Endogâmicos BALB C , Fagocitose
13.
J Dermatol ; 47(4): 409-412, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31960479

RESUMO

Chromoblastomycosis (CBM) is a fungal infection caused by fungi belonging to the order Chaetothyriales, and caused mainly by Fonsecaea pedrosoi. The classic treatment, based on itraconazole and/or terbinafine as well as physical approaches, is considered complex and ineffective due to the high rate of relapses. Thus, new strategies are needed to manage CBM; in this regard, the present work reports the evolution of lesions in patients successfully treated with imiquimod. Of note, classic treatment was not effective in healing the lesions of two of them, but single topical treatment with imiquimod healed the lesions.


Assuntos
Cromoblastomicose/tratamento farmacológico , Fonsecaea/isolamento & purificação , Imiquimode/administração & dosagem , Creme para a Pele/administração & dosagem , Adulto , Brasil , Cromoblastomicose/diagnóstico , Cromoblastomicose/microbiologia , Cromoblastomicose/patologia , Mãos , Humanos , Masculino , Pessoa de Meia-Idade , Pele/microbiologia , Pele/patologia , Resultado do Tratamento
14.
J Microbiol Methods ; 170: 105838, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31926179

RESUMO

Chromoblastomycosis (CBM) is a chronic cutaneous or subcutaneous mycosis that is prevalent worldwide. Though CBM tends not to be fatal, it is difficult to treat and complications can include chronic, marked lesions, lymphatic damage, and neoplastic transformation. Fonsecaea monophora, as a new species segregated from Fonsecaea pedrosoi, is the predominant causative pathogen of CBM in southern China. However, research about F. monophora has been limited, which may be due to a lack of an effective genetic manipulation system for F. monophora. In this study, we successfully established a random insertional mutagenesis system by Agrobacterium tumefaciens-mediated transformation (ATMT) in F. monophora for the first time. In order to improve the efficiency of ATMT, various co-culture conditions were optimized, including: acetosyringone (AS) concentrations, co-culture duration, ratio of bacteria to conidia, and the A. tumefaciens strains. In addition, thermal asymmetric interlaced polymerase chain reaction (TAIL-PCR) was performed to identify the transferred DNA (T-DNA) flanking sequences of the F. monophora transformants. The valuable transformants obtained in this study will be used for research in the future.


Assuntos
Agrobacterium tumefaciens/genética , DNA Bacteriano/genética , Farmacorresistência Fúngica/genética , Fonsecaea/genética , Transformação Genética/genética , Antibacterianos/farmacologia , Cromoblastomicose/microbiologia , Fonsecaea/efeitos dos fármacos , Higromicina B/farmacologia , Mutagênese Insercional/genética , Reação em Cadeia da Polimerase , Microbiologia do Solo
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