Abstract
BackgroundLeishmania 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.ResultsHere 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.ConclusionsTaken 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.
Highlights
Leishmania are obligated intracellular pathogens that replicate almost exclusively in macrophages
Light microscopy on Giemsa stained chamber slides of infected BMMs showed that the percentage of infected cells and the mean amastigote loads were comparable between L. major infected C57BL/6 and BALB/c bone marrow derived macrophages (BMdM) in each of the three experimental replicates used in this study (Table 1)
Of the 18 899 genes represented on the array, our analysis of mRNA expression in mice BMdM infected by live parasites showed that a total of 1175 genes were expressed differentially over the time course in BALB/c BMdM and approximately the same number of genes (1174) was differentially modulated (663 down- and 511 up-regulated) in C57BL/6 BMdM
Summary
Leishmania are obligated intracellular pathogens that replicate almost exclusively in macrophages. The outcome of infection depends largely on parasite pathogenicity and virulence and on the activation status and genetic background of macrophages. Animal models are essential for a better understanding of pathogenesis of different microbes and the cutaneous leishmaniasis murine model has been widely used to characterize the response against L. major. These studies have capitalized on two different mouse strains with contrasted behavior in response to parasite infection: the BALB/c mice which develop severe lesions at the site of cutaneous inoculation [8] and the C57BL/6 mice with a self-healing lesion [9,10]. In this study we compared the transcriptomic signature of BALB/c and C57BL/6 derived macrophages and investigated whether susceptibility or resistance to L. major might reflect differences in macrophage responses to this parasite
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
