Dual Role for Nitric Oxide in Paracoccidioidomycosis: Essential for Resistance, but Overproduction Associated with Susceptibility

Abstract

Using a murine model of susceptibility and resistance to paracoccidioidomycosis, we have previously demonstrated that immunosuppression occurs in susceptible (B10.A), but not in resistant (A/Sn), mouse strains. Accumulating evidence shows that NO is involved in the induction of T cell immunosuppression during infection as well as in the killing of Paracoccidioides brasiliensis. In the present work, we focused on NO and other macrophage products that could be associated with resistance or susceptibility to paracoccidioidomycosis. A striking difference was related to NO and TNF production. Macrophages from B10.A mice produced high and persistent NO levels, while in A/Sn animals, TNF production predominated. In in vitro cultures, P. brasiliensis-infected macrophages from A/Sn mice also produced large amounts of TNF, while B10.A macrophages only produced NO. TNF production by B10.A macrophages appeared to be suppressed by NO, because the addition of aminoguanidine sulfate, an inducible NO synthase (NOS2) inhibitor, resulted in TNF production. These results suggested that enhanced TNF or NO production is associated with resistance and susceptibility, respectively. However, regardless of the mouse strain, NOS2-deficient or aminoguanidine sulfate-treated mice presented extensive tissue lesions with increased fungal load in lungs and liver compared with their controls. We conclude that NOS2-derived NO is essential for resistance to paracoccidioidomycosis, but overproduction is associated with susceptibility.

Bacterial Lipopolysaccharide Signaling Through Toll-Like Receptor 4 Suppresses Asthma-Like Responses Via Nitric Oxide Synthase 2 Activity

“…Several pieces of evidence indicate that the biological activities of NO may vary depending on the NO concentration (low or high doses exert pro-or anti-inflammatory effects, respectively), the cell types, enzymes, and transcription factors involved (26,27,30). Our data suggest that high concentrations of NO are affecting different cell types such as T cells, eosinophils, mast cells, and bronchial epithelial cells.…”

“…Since LPS up-regulates NOS2 activity (27) and NO is involved in the suppression of many immunoinflammatory processes (26,27,30,35), we compared the effects of LPS on the Th2-dominated intrapulmonary immune responses of NOS2 Ϫ/Ϫ with WT mice. Fig.…”

“…Serum nitrite concentrations were determined by a spectrophotometric method based on the Griess reaction as previously described (30). Before analysis, nitrate was first converted to nitrite by incubation with nitrate reductase and NADPH (Boehringer Mannheim, Mannheim, Germany) for 6 h at 37°C.…”

Interleukin-15 augments oxidative metabolism and fungicidal activity of human monocytes against Paracoccidioides brasiliensis

“…In the present study, monocytes challenged with Pb18 released both pro and anti-inflammatory cytokines and cell activation with IL-15 induced high levels of TNF-α, the main cytokine involved in the effective killing of Pb18 in vitro , Carmo et al 2006. In experimental PCM models, persistent TNF-α production has been associated with resistance to Pb18 infection, which is also essential for the control of fungal dissemination (Bocca et al 1998, Souto et al 2000, Nascimento et al 2002.…”

Parallels in Fungal Pathogenesis on Plant and Animal Hosts

“…Commonalities of the defense systems of different hosts against fungal pathogens include programmed cell death and oxidative burst response (55,56). Animal-and plant-pathogenic microbes (fungal and bacterial) release molecules with pathogenicity-associated molecular patterns.…”