RESUMO
The thermally-dimorphic systemic fungal group includes several important human pathogens: Blastomyces dermatitides, Coccidioides immitis and C. posadasii, Histoplasma capsulatum, Paracoccidioides brasiliensis, P. lutzii, and Talaromyces (Penicillium) marneffei. They usually are geographically restricted and have natural habitats in soil or in plants, and when fungal propagules invade mammalian host by inhalation, they initiate an inflammatory reaction that can result in self-resolution of the infection or cause an acute or chronic disease. In the setting of the AIDS pandemic and the developments in modern medicine, such as immunosuppressive therapy in cancer surgery patients and in transplantation and autoimmune diseases, the incidence of endemic mycoses has progressively increased. Another important factor of the increased incidence of systemic mycoses in certain regions is the progressive devastation of tropical and subtropical forests. In this review, we focus on two of the most important systemic mycoses: paracoccidioidomycosis and histoplasmosis, and their major characteristics in epidemiology, clinical aspects and laboratorial diagnosis.
Assuntos
Antifúngicos/farmacologia , Histoplasma/efeitos dos fármacos , Histoplasmose/diagnóstico , Histoplasmose/tratamento farmacológico , Paracoccidioides/efeitos dos fármacos , Paracoccidioidomicose/diagnóstico , Paracoccidioidomicose/tratamento farmacológico , Antifúngicos/química , Histoplasma/isolamento & purificação , Histoplasmose/epidemiologia , Humanos , Testes de Sensibilidade Microbiana , Paracoccidioides/isolamento & purificação , Paracoccidioidomicose/epidemiologiaRESUMO
Paracoccidioidomycosis (PCM) is an endemic Latin American mycosis caused by Paracoccidioides brasiliensis and also by the recently described P. lutzii. The systemic mycosis is the 10th leading cause of death due to infectious diseases in Brazil. As published, 1,853 patients died of PCM in the 1996-2006 decade in this country. The main diagnostic antigen of P.brasiliensis is the 43 kDa glycoprotein gp43, and its 15-mer peptide QTLIAIHTLAIRYAN, known as P10, contains the T-CD4(+) epitope that elicits an IFN-γ-mediated Th1 immune response, which effectively treats mice intratracheally infected with PCM. The association of peptide P10 with antifungal drugs rendered an additive protective effect, even in immunosuppressed animals, being the basis of a recommended treatment protocol. Other immunotherapeutic tools include a peptide carrying a B cell epitope as well as protective anti-gp43 monoclonal antibodies. New delivery systems and gene therapy have been studied in prophylactic and therapeutic protocols to improve the efficacy of the recognized antigens aiming at a future vaccine as co-adjuvant therapy in patients with PCM.
RESUMO
Vaccination with peptide 10 (P10), derived from the Paracoccidioides brasiliensis glycoprotein 43 (gp43), induces a Th1 response that protects mice in an intratracheal P. brasiliensis infection model. Combining P10 with complete Freund's adjuvant (CFA) or other adjuvants further increases the peptide's antifungal effect. Since dendritic cells (DCs) are up to 1,000-fold more efficient at activating T cells than CFA, we examined the impact of P10-primed bone-marrow-derived DC vaccination in mice. Splenocytes from mice immunized with P10 were stimulated in vitro with P10 or P10-primed DCs. T cell proliferation was significantly increased in the presence of P10-primed DCs compared to the peptide. The protective efficacy of P10-primed DCs was studied in an intratracheal P. brasiliensis model in BALB/c mice. Administration of P10-primed DCs prior to (via subcutaneous vaccination) or weeks after (via either subcutaneous or intravenous injection) P. brasiliensis infection decreased pulmonary damage and significantly reduced fungal burdens. The protective response mediated by the injection of primed DCs was characterized mainly by an increased production of gamma interferon (IFN-γ) and interleukin 12 (IL-12) and a reduction in IL-10 and IL-4 compared to those of infected mice that received saline or unprimed DCs. Hence, our data demonstrate the potential of P10-primed DCs as a vaccine capable of both the rapid protection against the development of serious paracoccidioidomycosis or the treatment of established P. brasiliensis disease.
Assuntos
Células Dendríticas/imunologia , Vacinas Fúngicas/imunologia , Glicoproteínas/imunologia , Paracoccidioides/imunologia , Paracoccidioidomicose/prevenção & controle , Paracoccidioidomicose/terapia , Fragmentos de Peptídeos/imunologia , Vacinação/métodos , Animais , Proliferação de Células , Citocinas/metabolismo , Vacinas Fúngicas/administração & dosagem , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
The presence of bats in caves, attics, ceilings, and roofs is important epidemiologically as they can increase the chance of human acquisition of pathogens, including Histoplasma capsulatum. Brazilian urban areas contain many species of bats, especially insectivorous bats, that are attracted by a wide range of readily available food and shelter. From August 2003 to December 2008, we analysed 2427 bats in the São Paulo State region. Homogenates of the livers and spleens of the bats were plated on specific medium to identify animals infected with H. capsulatum. The fungus was isolated from 87 bats (3·6%). The infected bats were identified as Molossus molossus (74), Nyctinomops macrotis (10), Tadarida brasiliensis (1), Molossus rufus (1) and Eumops glaucinus (1), all insectivorous species. The data presented are a relevant contribution to the epidemiology of H. capsulatum in densely populated urban areas such as in São Paulo State, especially since histoplasmosis is not included in the mandatory disease notification system.
Assuntos
Quirópteros/microbiologia , Histoplasma/isolamento & purificação , Histoplasmose/veterinária , Animais , Brasil , Quirópteros/classificação , Feminino , Histoplasmose/microbiologia , Fígado/microbiologia , Masculino , Prevalência , Baço/microbiologiaRESUMO
Forty Cryptococcus gattii strains were submitted to antifungal susceptibility testing with fluconazole, itraconazole, amphotericin B and terbinafine. The minimum inhibitory concentration (MIC) ranges were 0.5-64.0 for fluconazole, <0.015-0.25 for itraconazole, 0.015-0.5 for amphotericin B and 0.062-2.0 for terbinafine. A bioassay for the quantitation of fluconazole in murine brain tissue was developed. Swiss mice received daily injections of the antifungal, and their brains were withdrawn at different times over the 14-day study period. The drug concentrations varied from 12.98 to 44.60 µg/mL. This assay was used to evaluate the therapy with fluconazole in a model of infection caused by C. gattii. Swiss mice were infected intracranially and treated with fluconazole for 7, 10 or 14 days. The treatment reduced the fungal burden, but an increase in fungal growth was observed on day 14. The MIC for fluconazole against sequential isolates was 16 µg/mL, except for the isolates obtained from animals treated for 14 days (MIC = 64 µg/mL). The quantitation of cytokines revealed a predominance of IFN-γ and IL-12 in the non-treated group and elevation of IL-4 and IL-10 in the treated group. Our data revealed the possibility of acquired resistance during the antifungal drug therapy.
Assuntos
Antifúngicos/farmacologia , Encéfalo/microbiologia , Infecções Fúngicas do Sistema Nervoso Central/tratamento farmacológico , Criptococose/tratamento farmacológico , Cryptococcus gattii/efeitos dos fármacos , Fluconazol/farmacologia , Animais , Antifúngicos/uso terapêutico , Infecções Fúngicas do Sistema Nervoso Central/microbiologia , Criptococose/microbiologia , Modelos Animais de Doenças , Farmacorresistência Fúngica , Fluconazol/uso terapêutico , Humanos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Resultado do TratamentoRESUMO
The fate of organochlorine 14C-dicofol in activated sludge process was investigated. Results showed that the major part of radioactivity remained adsorbed on biological sludge. Consequently, its final disposal deserves special attention. The small amounts of dicofol, biotransformed or not, which remained in the treated effluent could contaminate receiving bodies.
Glicoproteínas, glicoesfingolipídios e polissacarídios, expostos nas camadas mais externas da parede celular dos fungos, estão envolvidos em diferentes tipos de interações com o ambiente extracelular. Essas moléculas são componentes essenciais desses organismos, contribuindo para a estrutura, integridade, crescimento celular, diferenciação e sinalização. Alguns são compostos imunologicamente ativos com potencial para regular a patogênese e a resposta imune do hospedeiro, Algumas dessas estruturas podem ser especificamente reconhecidas por anticorpos presentes no soro de pacientes, sugerindo uma possível utilização como ferramenta no diagnóstico das infecções fúngicas.
Assuntos
Humanos , Diferenciação Celular , Crescimento Celular , Parede Celular , Fungos , Glicoconjugados , Imunidade nas Mucosas , Técnicas In Vitro , Micoses , Polissacarídeos , Métodos , Pacientes , Técnicas e Procedimentos DiagnósticosRESUMO
The protective role of specific antibodies against Paracoccidioides brasiliensis is controversial. In the present study, we analyzed the effects of monoclonal antibodies on the major diagnostic antigen (gp43) using in vitro and in vivo P. brasiliensis infection models. The passive administration of some monoclonal antibodies (MAbs) before and after intratracheal or intravenous infections led to a reduced fungal burden and decreased pulmonary inflammation. The protection mediated by MAb 3E, the most efficient MAb in the reduction of fungal burden, was associated with the enhanced phagocytosis of P. brasiliensis yeast cells by J774.16, MH-S, or primary macrophages. The ingestion of opsonized yeast cells led to an increase in NO production by macrophages. Passive immunization with MAb 3E induced enhanced levels of gamma interferon in the lungs of infected mice. The reactivity of MAb 3E against a panel of gp43-derived peptides suggested that the sequence NHVRIPIGWAV contains the binding epitope. The present work shows that some but not all MAbs against gp43 can reduce the fungal burden and identifies a new peptide candidate for vaccine development.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos de Fungos/imunologia , Proteínas Fúngicas/imunologia , Glicoproteínas/imunologia , Paracoccidioides/patogenicidade , Paracoccidioidomicose/imunologia , Paracoccidioidomicose/prevenção & controle , Traqueia/microbiologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Antígenos de Fungos/química , Linhagem Celular , Células Cultivadas , Epitopos/química , Proteínas Fúngicas/química , Glicoproteínas/química , Imunização Passiva , Injeções Intravenosas , Macrófagos Alveolares/microbiologia , Macrófagos Peritoneais/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Paracoccidioides/imunologia , Paracoccidioidomicose/diagnóstico , Paracoccidioidomicose/parasitologia , Fagocitose , Resultado do TratamentoRESUMO
Ajoene has been described as an antithrombotic, anti-tumour, antifungal, antiparasitic and antibacterial agent. This study deals with the efficacy of ajoene to treat mice intratracheally infected with Paracoccidioides brasiliensis. The results indicate that ajoene therapy is effective in association with antifungal drugs (sulfametoxazol/trimethoprim), showing a positive additive effect. Ajoene-treated mice developed Th1-type cytokine responses producing higher levels of IFN-gamma and IL-12 when compared to the infected but untreated members of the control group. Antifungal activity of ajoene involves a direct effect on fungi and a protective pro-inflammatory immune response. Reduction of fungal load is additive to chemotherapy and therefore the combined treatment is mostly effective against experimental paracoccidioidomycosis.