RESUMO
The microsporidia are a large group of intracellular parasites with a broad range of hosts, including humans. Encephalitozoon intestinalis is the second microsporidia species most frequently associated with gastrointestinal disease in humans, especially immunocompromised or immunosuppressed individuals, including children and the elderly. The prevalence reported worldwide in these groups ranges from 0 to 60%. Currently, albendazole is most commonly used to treat microsporidiosis caused by Encephalitozoon species. However, the results of treatment are variable, and relapse can occur. Consequently, efforts are being directed toward identifying more effective drugs for treating microsporidiosis, and the study of new molecular targets appears promising. These parasites lack mitochondria, and oxidative phosphorylation therefore does not occur, which suggests the enzymes involved in glycolysis as potential drug targets. Here, we have for the first time characterized the glycolytic enzyme triosephosphate isomerase of E. intestinalis at the functional and structural levels. Our results demonstrate the mechanisms of inactivation of this enzyme by thiol-reactive compounds. The most striking result of this study is the demonstration that established safe drugs such as omeprazole, rabeprazole and sulbutiamine can effectively inactivate this microsporidial enzyme and might be considered as potential drugs for treating this important disease.
Assuntos
Albendazol/uso terapêutico , Proteínas Fúngicas/antagonistas & inibidores , Microsporídios/efeitos dos fármacos , Microsporidiose/tratamento farmacológico , Triose-Fosfato Isomerase/antagonistas & inibidores , Sequência de Aminoácidos , Encephalitozoon/efeitos dos fármacos , Encephalitozoon/enzimologia , Encephalitozoon/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/microbiologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Humanos , Microsporídios/enzimologia , Microsporídios/genética , Microsporidiose/microbiologia , Omeprazol/uso terapêutico , Rabeprazol/uso terapêutico , Homologia de Sequência de Aminoácidos , Tiamina/análogos & derivados , Tiamina/uso terapêutico , Triose-Fosfato Isomerase/genética , Triose-Fosfato Isomerase/metabolismoRESUMO
INTRODUCTION: Encephalitozoon intestinalis, a parasite belonging to the phylum Microsporidia, is causes gastrointestinal infections in the immunocompromised host. A suitable pharmacologically immunosuppressed animal model for the study of natural E. intestinalis infection, which can establish the immune components that respond to this parasite, is lacking. OBJECTIVE: To evaluate the effect of immunosuuppression with Cyclosporine A (CsA) in C57BL/ 6 mice on experimental infection with E. intestinalis infection. MATERIALS AND METHODS: Eighty C57BL/6 mice were distributed in four treatment groups: Control, CsA-immunosuppressed mice without infection, immunocompetent and immunossuppressed mice infected with E. intestinalis. Mice were immunosuppressed with a weekly dose of 50 mg/Kg body weight of CsA, during the course of the study. Five mice from each group were sacrificed 2, 3, 4 and 6 weeks post-infection, to obtain blood for antibody testing and stool samples were analyzed to assess excretion of spores. RESULTS: Production of specific IgG antibodies was significantly higher in the immunocompetent group as compared to the immunosuppressed group of experimentally infected mice. In the infected mice, parasites were not observed in any tissues different from the small intestine. However, spore excretion through the stool and duodenal liquid was higher in the group of immunosuppresed infected mice. CONCLUSION: Immunosuppression induced with CsA in the murine model did not allow parasite dissemination and illness progression, but raised kinetics of spore excretion and decreased the production of IgG antibodies.