Detrimental role of endogenous nitric oxide in host defence against Sporothrix schenckii

Abstract

SummaryWe 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 wildtype (WT) mice treated with Nx-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-a production by spleen cells. In addition, fungicidal activity and NO production by interferon-c (IFN-c) 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-c Interestingly, macrophages from these groups of mice presented fungicidal activity after in vitro stimulation with higher doses of IFN-c. 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.

Sporothrix schenckii and Sporotrichosis

“…Although nitric oxide is a fungicidal molecule, this compound may be implicated in immunosuppression in vivo, because high levels of TNF-␣ and NO released after yeast dissemination into the tissues lead to the induction of molecules suppressing T cell responses, such as interleukin10 (IL-10), FasL, and CTLA-4. This deleterious effect of NO occurs just upon initial infection, becoming crucial some time after fungal inoculation (68). In fact, TNF-␣ production drastically subsides at 4 to 6 weeks after experimental infection, inducing the fungus to reproduce and infect host tissues.…”

Cell surface expression of adhesins for fibronectin correlates with virulence in Sporothrix schenckii

“…In the present work, the virulence in C57BL/6 mice, an animal model previously developed in our laboratory (Fernandes et al, 2000) and validated by other groups (Fernandes et al, 2008), and adherence capacity to fibronectin of several S. schenckii isolates were compared. The data obtained demonstrated that S. schenckii isolates recovered from different clinical forms of sporotrichosis and one environmental isolate showed distinct virulence levels in a murine model.…”

Esporotricosis y cromoblastomicosis: revisión de la literatura

“…Una vez el hongo está en el órgano diana, éste induce una reacción granulomatosa supurativa en los tejidos del huésped, siendo la inmunidad de células T dependientes de óxido nítrico muy importante para lograr el control de la enfermedad (17).…”