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Updated: May 6, 2026
Quantification of Intracellular Growth Inside Macrophages is a Fast and Reliable Method for Assessing the Virulence of Leishmania Parasites
Published on: March 16, 2018
Comparative analysis of resistant and susceptible macrophage gene expression response to Leishmania major parasite
Imen Rabhi, Sameh Rabhi, Rym Ben-Othman
1Institut Pasteur de Tunis, Parasitologies medicales biotechnologies et Biomolecules, 13, Place Pasteur - B, P, 74,, 1002 Tunis-Belvedere, Tunisia. lamia.guizani@Pasteur.rns.tn.
Background:
Leishmania are obligated intracellular pathogens that replicate almost exclusively in macrophages. The outcome of infection depends largely on parasite pathogenicity and virulence but also on the activation status and genetic background of macrophages. Animal models are essential for a better understanding of pathogenesis of different microbes including Leishmania.
Results:
Here we compared the transcriptional signatures of resistant (C57BL/6) and susceptible (BALB/c) mouse bone marrow-derived macrophages in response to Leishmania major (L. major) promastigotes infection.Microarray results were first analyzed for significant pathways using the Kyoto Encylopedia of Genes and Genomes (KEGG) database. The analysis revealed that a large set of the shared genes is involved in the immune response and that difference in the expression level of some chemokines and chemokine receptors could partially explain differences in resistance. We next focused on up-regulated genes unique to either BALB/c or C57BL/6 derived macrophages and identified, using KEGG database, signal transduction pathways among the most relevant pathways unique to both susceptible and resistant derived macrophages. Indeed, genes unique to C57BL/6 BMdMs were associated with target of rapamycin (mTOR) signaling pathway while a range of genes unique to BALB/c BMdMs, belong to p53 signaling pathway. We next investigated whether, in a given mice strain derived macrophages, the different up-regulated unique genes could be coordinately regulated. Using GeneMapp Cytoscape, we showed that the induced genes unique to BALB/c or C57BL/6 BMdMs are interconnected. Finally, we examined whether the induced pathways unique to BALB/c derived macrophages interfere with the ones unique to C57BL/6 derived macrophages. Protein-protein interaction analysis using String database highlights the existence of a cross-talk between p53 and mTOR signaling pathways respectively specific to susceptible and resistant BMdMs.
Conclusions:
Taken together our results suggest that strains specific pathogenesis may be due to a difference in the magnitude of the same pathways and/or to differentially expressed pathways in the two mouse strains derived macrophages. We identify signal transduction pathways among the most relevant pathways modulated by L. major infection, unique to BALB/c and C57BL/6 BMdM and postulate that the interplay between these potentially interconnected pathways could direct the macrophage response toward a given phenotype.
Insights
Leishmania major infection elicits distinct macrophage transcriptional responses in resistant (C57BL/6) and susceptible (BALB/c) mice. These differences, involving unique signaling pathways like mTOR and p53, may explain varying host resistance to leishmaniasis.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Leishmania are intracellular pathogens that infect macrophages.
- Macrophage activation and genetic background influence infection outcomes.
- Animal models are crucial for understanding leishmaniasis pathogenesis.
Purpose of the Study:
- Compare transcriptional signatures of resistant and susceptible mouse macrophages upon Leishmania major infection.
- Identify key signaling pathways and gene expression differences contributing to host resistance.
- Investigate the interplay between unique pathways in different macrophage types.
Main Methods:
- Microarray analysis of bone marrow-derived macrophages (BMdMs) from C57BL/6 and BALB/c mice infected with L. major.
- Pathway analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG) database.
- Gene network analysis using GeneMapp Cytoscape and protein-protein interaction analysis using String database.
Main Results:
- Shared genes involved in immune response; differences in chemokine/receptor expression may explain resistance.
- Unique pathways identified: mTOR signaling in resistant (C57BL/6) BMdMs and p53 signaling in susceptible (BALB/c) BMdMs.
- Interconnectedness of unique genes and a cross-talk between p53 and mTOR pathways observed.
Conclusions:
- Strain-specific pathogenesis of leishmaniasis may result from differential pathway magnitudes or expression.
- Signal transduction pathways, particularly p53 and mTOR, are significantly modulated by L. major infection.
- Interplay between these pathways likely directs macrophage response and influences leishmaniasis outcome.
