Inducible nitric oxide synthase-deficient mice show exacerbated inflammatory process and high production of both Th1 and Th2 cytokines during paracoccidioidomycosis.
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.
Livonesi
Márcia Cristina
MC
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>
Rossi
Marcos A
MA
de Souto
Janeusa Trindade
JT
Campanelli
Ana Paula
AP
de Sousa
Ricardo Luiz Moro
RL
Maffei
Cláudia M Leite
CM
Ferreira
Beatriz Rossetti
BR
Martinez
Roberto
R
da Silva
João Santana
JS
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
D016207:Cytokines; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II