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Induction of macrophage parasiticidal activity by Staphylococcus aureus and exotoxins through the nitric oxide
Abstract:
Murine peritoneal macrophages stimulated in vitro with killed Gram-positive bacteria Staphylococcus aureus or its membrane components in the presence of interferon-gamma (IFN-gamma) expressed high levels of nitric oxide (NO) synthase and produced large amounts of NO in a dose-dependent manner. This is not due to the contamination by Gram-negative endotoxin because the stimulatory activity was not affected by the addition of polymyxin B. The expression of the NO synthase and the synthesis of NO by macrophages stimulated with toxic shock syndrome toxin-1 (TSST), lipoteichoic acid (LTA) or killed whole S. aureus together with IFN-gamma was inhibited by the glucocorticoid, dexamethasone or by the specific inhibitor of NO synthesis, L-N-iminoethyl-ornithine (L-NIO). The exotoxins together with IFN-gamma also activated macrophages to kill the intracellular parasite Leishmania major. The leishmanicidal activity was completely inhibited by L-NIO.
Insights
Gram-positive bacteria Staphylococcus aureus and its toxins, when combined with interferon-gamma (IFN-gamma), induce macrophages to produce nitric oxide (NO) and kill Leishmania major parasites. This NO production is crucial for the parasite-killing activity.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Macrophages are key immune cells involved in pathogen defense.
- Gram-positive bacteria like Staphylococcus aureus can activate immune responses.
- Nitric oxide (NO) is a molecule with diverse roles in immunity and inflammation.
Purpose of the Study:
- To investigate the role of Staphylococcus aureus components in activating macrophages.
- To determine the production of nitric oxide (NO) by macrophages stimulated with Gram-positive bacteria.
- To assess the impact of NO on macrophage-mediated killing of Leishmania major.
Main Methods:
- Murine peritoneal macrophages were stimulated in vitro with killed S. aureus, its membrane components, or exotoxins (TSST, LTA) alongside interferon-gamma (IFN-gamma).
- Nitric oxide synthase (NOS) expression and NO production were measured.
- Macrophage activity against Leishmania major was assessed.
- Inhibitors like polymyxin B, dexamethasone, and L-N-iminoethyl-ornithine (L-NIO) were used to probe mechanisms.
Main Results:
- Stimulation with S. aureus or its components plus IFN-gamma led to high levels of NO synthase expression and dose-dependent NO production.
- Polymyxin B did not affect stimulatory activity, ruling out Gram-negative endotoxin contamination.
- Dexamethasone and L-NIO inhibited NO synthesis.
- Exotoxins plus IFN-gamma activated macrophages to kill Leishmania major, an effect completely blocked by L-NIO.
Conclusions:
- Gram-positive bacterial components, particularly exotoxins, in conjunction with IFN-gamma, induce significant NO production in macrophages.
- Macrophage-derived NO plays a critical role in the killing of intracellular parasites like Leishmania major.
- This study highlights a mechanism by which Gram-positive bacteria can modulate macrophage function for pathogen clearance.