title: Detrimental role of endogenous nitric oxide in host defence against Sporothrix schenckii.
abstract: We earlier demonstrated that nitric oxide (NO) is a fungicidal molecule against Sporothrix schenckii in vitro. In the present study we used mice deficient in inducible nitric oxide synthase (iNOS-/-) and C57BL/6 wild-type (WT) mice treated with Nomega-nitro-arginine (Nitro-Arg-treated mice), an NOS inhibitor, both defective in the production of reactive nitrogen intermediates, to investigate the role of endogenous NO during systemic sporotrichosis. When inoculated with yeast cells of S. schenckii, WT mice presented T-cell suppression and high tissue fungal dissemination, succumbing to infection. Furthermore, susceptibility of mice seems to be related to apoptosis and high interleukin-10 and tumour necrosis factor-alpha production by spleen cells. In addition, fungicidal activity and NO production by interferon-gamma (IFN-gamma) and lipopolysaccharide-activated macrophages from WT mice were abolished after fungal infection. Strikingly, iNOS-/- and Nitro-Arg-treated mice presented fungal resistance, controlling fungal load in tissues and restoring T-cell activity, as well as producing high amounts of IFN-gamma Interestingly, macrophages from these groups of mice presented fungicidal activity after in vitro stimulation with higher doses of IFN-gamma. Herein, these results suggest that although NO was an essential mediator to the in vitro killing of S. schenckii by macrophages, the activation of NO system in vivo contributes to the immunosuppression and cytokine balance during early phases of infection with S. schenckii.
authors.affiliation: Department of Pharmacology, School of Medicine Ribeirão Preto, Unviersity of São Paulo, São Paulo, Brazil. fernandeskss@yahoo.com.br
authors.forename: Karla Simone S
authors.initials: KS
authors.lastname: Fernandes
authors.forename: Edward Helal
authors.initials: EH
authors.lastname: Neto
authors.forename: Marcelly M S
authors.initials: MM
authors.lastname: Brito
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Christina
authors.initials: C
authors.lastname: Barja-Fidalgo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D019335:Nitroarginine / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013154:Spleen / Q000276:immunology; D013175:Sporothrix / Q000254:growth & development / Q000302:isolation & purification; D013174:Sporotrichosis / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D019335:Nitroarginine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II