Inducible nitric oxide synthase-deficient mice show exacerbated inflammatory process and high production of both Th1 and Th2 cytokines during paracoccidioidomycosis |
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| Institution: | 1. Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Departamento de Bioquímica e Imunologia, Avenida Bandeirantes, 3900, Ribeirão Preto, SP, CEP 14049-900, Brazil;2. Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Departamento de Patologia, Avenida Bandeirantes, 3900, CEP 14049-900 Ribeirão Preto, SP, Brazil;3. Universidade Federal do Rio Grande do Norte, Centro de Biociências, Campus Universitário BR 101, Lagoa Nova, CEP 59072-970 Natal, RN, Brazil;4. Faculdade de Odontologia de Bauru, Universidade de São Paulo, Departamento de Ciências Biológicas, Al. Octávio Pinheiro Brisola, 9-75, CEP 17012-901 Bauru, SP, Brazil;5. Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Departamento de Ciências Básicas, Avenida Duque de Caxias Norte, 225, CEP 13635-900 Pirassununga, SP, Brazil;6. Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Avenida Bandeirantes, 3900, CEP 14049-900 Ribeirão Preto, SP, Brazil;7. Escola de Enfermagem de Ribeirão Preto, Universidade de São Paulo, Departamento de Enfermagem Materno-infantil e Saúde Pública, Avenida Bandeirantes, 3900, CEP 14040-902 Ribeirão Preto, SP, Brazil;8. Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Departamento de Clínica Médica, 6° andar do Hospital das Clínicas, Avenida Bandeirantes, 3900, CEP 14048-900 Ribeirão Preto, SP, Brazil;1. Chair of Chemistry of Biogenic Resources, Technical University of Munich, Schulgasse 16, 94315 Straubing, Germany;2. Evonik Nutrition and Care GmbH, Goldschmidtstraße 100, 45127 Essen, Germany;1. Xiamen Key Laboratory of Chiral Drugs, Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China;2. School of Biomedical of Science, Institute Molecular Medicine, Huaqiao University, Quanzhou, China;3. Department of Pharmacy, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, China;1. Laboratory of Inflammatory Genes, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil;2. Department of Microbiology & Immunology, Columbia University, College of Physicians and Surgeons, New York, NY 10031, USA;3. New York Genome Center, New York, NY 10013, USA |
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| Abstract: | Paracoccidioidomycosis, the major systemic mycosis in Latin America, is caused by fungus Paracoccidioides brasiliensis. To analyze the influence of inducible nitric oxide synthase (iNOS) in this disease, iNOS-deficient (iNOS?/?) and wild-type (WT) mice were infected intravenously with P. brasiliensis 18 isolate. We found that, unlike WT mice, iNOS?/? mice did not control fungal proliferation, and began to succumb to infection by day 50 after inoculation of yeast cells. Typical inflammatory granulomas were found in WT mice, while, iNOS?/? mice presented incipient granulomas with intense inflammatory process and necrosis. Additionally, splenocytes from iNOS?/? mice did not produce nitric oxide, however, their proliferative response to Con-A was impaired, just like infected WT mice. Moreover, infected iNOS?/? mice presented a mixed pattern of immune response, releasing high levels of both Th1 (IL-12, IFN-γ and TNF-α) and Th2 (IL-4 and IL-10) cytokines. These data suggest that the enzyme iNOS is a resistance factor during paracoccidioidomycosis by controlling fungal proliferation, by influencing cytokines production, and by appeasing the development of a high inflammatory response and consequently formation of necrosis. However, iNOS-derived nitric oxide seems not being the unique factor responsible for immunosuppression observed in infections caused by P. brasiliensis. |
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