title: Inducible nitric oxide synthase-deficient mice show exacerbated inflammatory process and high production of both Th1 and Th2 cytokines during paracoccidioidomycosis.
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-gamma and TNF-alpha) 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.
authors.affiliation: 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. mclivonesi@yahoo.com.br <mclivonesi@yahoo.com.br>
authors.forename: Márcia Cristina
authors.initials: MC
authors.lastname: Livonesi
authors.forename: Marcos A
authors.initials: MA
authors.lastname: Rossi
authors.forename: Janeusa Trindade
authors.initials: JT
authors.lastname: de Souto
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Campanelli
authors.forename: Ricardo Luiz Moro
authors.initials: RL
authors.lastname: de Sousa
authors.forename: Cláudia M Leite
authors.initials: CM
authors.lastname: Maffei
authors.forename: Beatriz Rossetti
authors.initials: BR
authors.lastname: Ferreira
authors.forename: Roberto
authors.initials: R
authors.lastname: Martinez
authors.forename: João Santana
authors.initials: JS
authors.lastname: da Silva
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D006099:Granuloma / Q000276:immunology / Q000382:microbiology; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency; D010228:Paracoccidioides / Q000472:pathogenicity*; D010229:Paracoccidioidomycosis / Q000276:immunology / Q000382:microbiology; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism
chemical_list: D016207:Cytokines; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II