Leishmania Parasites Differently Regulate Antioxidant Genes in Macrophages Derived From Resistant and Susceptible
Haifa Bichiou1,2, Sameh Rabhi1, Cherif Ben Hamda1
1Laboratory of Medical Parasitology, Biotechnology and Biomolecules, Institut Pasteur de Tunis, Tunis-Belvedere, Tunisia.
Abstract:
Macrophage-Leishmania interactions are central to parasite growth and disease outcome. Macrophages have developed various strategies to fight invaders, including oxidative burst. While some microorganisms seem to survive and even thrive in an oxidative environment, others are susceptible and get killed. To counter oxidative stress, macrophages switch the expressions of cytoprotective and detoxifying enzymes, which are downstream targets of the nuclear factor erythroid 2-related factor 2 (Nrf2), to enhance cell survival. We have explored the transcription of NRF2 and of its target genes and compared the effect of the parasite on their transcription in bone marrow-derived macrophages (BMdMs) from Leishmania-resistant and Leishmania-susceptible mice. While heme oxygenase 1 (HO-1) transcription is independent of the genetic background, the transcription of glutathione reductase (Gsr) and of cysteine/glutamate exchange transporter (Slc7a11), involved in glutathione accumulation, was differentially regulated in BMdMs from both mouse strains. We also show that, except for HO-1, known to favor the survival of the parasite, the transcription of the selected genes, including Gsr, CD36, and catalase (CAT), was actively repressed, if not at all time points at least at the later ones, by the parasite, especially in Balb/c BMdMs. Consistent with these results, we found that the silencing of NRF2 in this study increases the survival and multiplication of the parasite.
Insights
Leishmania parasites manipulate macrophage defenses by repressing key antioxidant genes, including those regulated by nuclear factor erythroid 2-related factor 2 (Nrf2). Silencing Nrf2 enhances parasite survival, highlighting its role in controlling Leishmania infection.
Area of Science:
- Immunology
- Molecular Biology
- Parasitology
Background:
- Macrophage-Leishmania interactions are critical for disease progression.
- Macrophages employ oxidative burst and antioxidant defenses to combat pathogens.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates cytoprotective enzymes against oxidative stress.
Purpose of the Study:
- To investigate the transcriptional regulation of Nrf2 and its target genes during Leishmania infection.
- To compare the effects of Leishmania on Nrf2 pathway gene transcription in resistant versus susceptible mice.
- To determine the role of Nrf2 in controlling Leishmania parasite survival and multiplication.
Main Methods:
- Analysis of NRF2 and target gene transcription in bone marrow-derived macrophages (BMdMs) from Leishmania-resistant and -susceptible mice.
- Comparison of gene expression patterns at different time points post-infection.
- Assessment of Leishmania parasite survival and multiplication following NRF2 silencing.
Main Results:
- Heme oxygenase 1 (HO-1) transcription was independent of mouse genetic background.
- Glutathione reductase (Gsr) and Slc7a11 transcription were differentially regulated based on genetic background.
- Leishmania actively repressed transcription of Gsr, CD36, and catalase (CAT), but not HO-1, especially in susceptible (Balb/c) mice.
- Silencing of NRF2 significantly increased Leishmania parasite survival and multiplication.
Conclusions:
- Leishmania parasites actively suppress macrophage antioxidant defenses regulated by Nrf2.
- Differential regulation of Nrf2 target genes contributes to varying susceptibility to Leishmania infection.
- Nrf2 plays a crucial role in controlling Leishmania parasite burden within macrophages.
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