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Leishmania major parasites induced macrophage tolerance: implication of MAPK and NF-kappaB pathways
Rym Ben-Othman1, Koussay Dellagi, Lamia Guizani-Tabbane
1Laboratory of Immunopathology, Vaccinology and Molecular Genetics (LIVGM), WHO Collaborating Center for Research and Training in Leishmaniasis and Laboratoire International Associé Ingenierie Biomoléculaire-(LIA-CNRS), Institut Pasteur de Tunis, Tunis-Belvedere, Tunisia.
Abstract:
During infection pathogens elicit early inflammatory events and modulate mediators of the host inflammatory response. We show in the present study that the two stages of the Leishmania parasite differentially modulate the production of inflammatory cytokines with amastigotes inducing cytokine production but not promastigotes. However once they infect macrophages both stages were able to induce a state of tolerance characterized by the inhibition of TNFalpha production in response to a subsequent contact with the parasite. This effect was not due to the action of soluble deactivating cytokines released in the supernatant, but likely reflect direct cell-parasite interactions. Moreover, we show that parasite viability is required for macrophage tolerisation. Cross-stimulation experiments using two stimuli namely Leishmania and LPS, demonstrated a hierarchy of signalling with LPS mediating abrogation of Leishmania tolerance but not vice versa. Indeed, while LPS was able to overcome Leishmania induced tolerance LPS induced cell tolerance was refractory to subsequent Leishmania stimulation. This state of tolerance correlates with the hypo responsiveness of MAPK transduction pathways and defective activation of NF-kappaB transcription factor.
Insights
Leishmania parasites, specifically amastigotes, induce immune tolerance in macrophages by inhibiting TNF-alpha production. This tolerance, mediated by direct cell-parasite interactions, requires viable parasites and affects inflammatory signaling pathways.
Area of Science:
- Immunology
- Parasitology
- Cell Biology
Background:
- Pathogens trigger inflammatory responses during infection.
- Leishmania parasites exist in two forms: promastigotes and amastigotes.
- Understanding host-pathogen interactions is crucial for controlling infectious diseases.
Purpose of the Study:
- To investigate how Leishmania parasite stages modulate host inflammatory cytokine production.
- To elucidate the mechanisms underlying Leishmania-induced immune tolerance in macrophages.
- To determine the role of parasite viability and cell-cell interactions in this tolerance.
Main Methods:
- Differential cytokine production analysis between Leishmania amastigotes and promastigotes.
- Macrophage infection assays to assess tolerance induction.
- Supernatant analysis to rule out soluble deactivating factors.
- Parasite viability assays.
- Cross-stimulation experiments with Leishmania and lipopolysaccharide (LPS).
- Analysis of mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) signaling pathways.
Main Results:
- Leishmania amastigotes induce cytokine production, while promastigotes do not.
- Both parasite stages induce macrophage tolerance, inhibiting TNF-alpha production upon re-exposure.
- Tolerance is mediated by direct cell-parasite interactions, not soluble factors.
- Parasite viability is essential for inducing macrophage tolerance.
- LPS can overcome Leishmania-induced tolerance, but Leishmania cannot overcome LPS-induced tolerance.
- Leishmania-induced tolerance is associated with hyporesponsive MAPK pathways and defective NF-kappaB activation.
Conclusions:
- Leishmania parasites differentially modulate inflammatory responses based on their stage.
- Leishmania infection establishes a state of immune tolerance in macrophages, crucial for parasite survival.
- This tolerance involves direct parasite-host cell interactions and specific immune signaling pathway dysregulation.
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