Abstract
We analyzed the transcriptional signatures of mouse bone marrow-derived macrophages at different times after infection with promastigotes of the protozoan parasite Leishmania major. Ingenuity Pathway Analysis revealed that the macrophage metabolic pathways including carbohydrate and lipid metabolisms were among the most altered pathways at later time points of infection. Indeed, L. major promastiogtes induced increased mRNA levels of the glucose transporter and almost all of the genes associated with glycolysis and lactate dehydrogenase, suggesting a shift to anaerobic glycolysis. On the other hand, L. major promastigotes enhanced the expression of scavenger receptors involved in the uptake of Low-Density Lipoprotein (LDL), inhibited the expression of genes coding for proteins regulating cholesterol efflux, and induced the synthesis of triacylglycerides. These data suggested that Leishmania infection disturbs cholesterol and triglycerides homeostasis and may lead to cholesterol accumulation and foam cell formation. Using Filipin and Bodipy staining, we showed cholesterol and triglycerides accumulation in infected macrophages. Moreover, Bodipy-positive lipid droplets accumulated in close proximity to parasitophorous vacuoles, suggesting that intracellular L. major may take advantage of these organelles as high-energy substrate sources. While the effect of infection on cholesterol accumulation and lipid droplet formation was independent on parasite development, our data indicate that anaerobic glycolysis is actively induced by L. major during the establishment of infection.
Highlights
Leishmania, the causative agent of vector-borne diseases, known as leishmaniases, lives as an obligate intracellular parasite within mammalian hosts
In order to have a general and dynamic picture of the complex biological events that are acting in the context of Leishmania intracellular parasitism, we investigated the mouse macrophage response to initial invasion of L. major over a time course that extended from one to 24 hours post-infection
Of the 18 899 genes represented on the array, our analysis of mRNA expression in mouse BMdM infected by live parasites showed that a total of 782 genes were expressed differentially over the time course while only 375 genes were differentially modulated by macrophages infected by heat-inactivated promastigotes
Summary
Leishmania, the causative agent of vector-borne diseases, known as leishmaniases, lives as an obligate intracellular parasite within mammalian hosts. Different previous studies have used microarray technology to investigate the responses of macrophages from human and mouse origins to Leishmania infection [1], [2], [3], [4]. Most of these studies have dealt essentially with established infection, and limited responses to various species of Leishmania were observed. Hierarchical Clustering was performed to identify gross gene expression features and Ingenuity Pathway Analysis (IPA) was used to flag the mouse biological pathways, networks, and functions significantly altered by Leishmania infection during the first 24 hours post-infection
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