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Published on: March 16, 2018
Leishmania donovani lipophosphoglycan selectively inhibits signal transduction in macrophages
A Descoteaux1, S J Turco, D L Sacks
1Institute of Parasitology, McGill University, Macdonald Campus, Ste-Anne de Bellevue, QC, Canada.
Abstract:
The effect of purified lipophosphoglycan (LPG) of Leishmania donovani on signal transduction and gene expression in murine bone marrow-derived macrophages was investigated. LPG stimulated the rapid expression of both c-fos and TNF genes within 30 min after exposure, suggesting that the interaction of LPG with its receptor stimulated a specific signal transduction pathway. Macrophages pretreated with LPG for 3 h became unresponsive to subsequent stimulation with LPS and the activators of protein kinase C, 1-oleoyl-2-acetyl-glycerol, and calcium ionophore A23187. Moreover, LPG induced a rapid down-modulation of TNF receptors. In contrast, the ability of macrophages to express the c-fos gene in response to the cAMP analogue, dibutyryl cAMP, was not impaired by LPG. Fragmentation of LPG revealed that the inhibitory activity of LPG required both the repeating phosphorylated disaccharides and the phosphosaccharide core. Collectively, these data demonstrate that LPG selectively impaired signal transduction in macrophages and suggest a role for this molecule in the survival of the parasite within the macrophage.
Insights
Lipophosphoglycan (LPG) from Leishmania donovani selectively impairs macrophage signal transduction and gene expression. This molecule may play a crucial role in parasite survival within host macrophages.
Area of Science:
- Immunology
- Parasitology
- Molecular Biology
Background:
- Leishmania donovani is an intracellular parasite that infects macrophages.
- Lipophosphoglycan (LPG) is a major surface glycolipid of Leishmania parasites.
- Understanding LPG's interaction with host cells is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the effects of Leishmania donovani LPG on signal transduction pathways in murine bone marrow-derived macrophages.
- To determine the impact of LPG on macrophage gene expression, specifically c-fos and TNF.
- To elucidate the structural components of LPG responsible for its biological activity.
Main Methods:
- Purified Leishmania donovani LPG was used to treat murine bone marrow-derived macrophages.
- Gene expression analysis (c-fos, TNF) was performed using quantitative methods.
- Macrophage responsiveness to subsequent stimuli (LPS, PKC activators, calcium ionophore) was assessed.
- TNF receptor expression was monitored.
- LPG fragmentation was employed to identify active domains.
Main Results:
- LPG rapidly stimulated c-fos and TNF gene expression within 30 minutes.
- Pre-treatment with LPG rendered macrophages unresponsive to LPS, protein kinase C activators, and calcium ionophore.
- LPG induced down-modulation of TNF receptors.
- Macrophage response to cAMP analogue (dibutyryl cAMP) remained unaffected.
- Inhibitory activity of LPG was dependent on both repeating phosphorylated disaccharides and the phosphosaccharide core.
Conclusions:
- Leishmania donovani LPG selectively impairs signal transduction pathways in macrophages.
- LPG's ability to modulate macrophage responses suggests a role in parasite persistence.
- The specific structural elements of LPG are essential for its immunomodulatory functions.
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