Itaconate: A Nexus Metabolite Fueling Leishmania Survival Through Lipid Metabolism Modulation

Abstract

Leishmaniasis, caused by the Leishmania parasite, is a neglected public health issue. Leishmania mainly infects macrophages, where metabolic reprogramming shapes their plasticity (M1/M2), affecting the host's resistance or susceptibility to infection. The development of this infection is influenced by immune responses, with an excessive anti-inflammatory reaction linked to negative outcomes through the modulation of various mediators. Itaconate, produced by the Acod1 gene, is recognized for its anti-inflammatory effects, but its function in leishmaniasis is not well understood. This study aimed to investigate the potential role of itaconate in leishmaniasis. Using transcriptomic data from L. major-infected BMDMs, we assessed the expression dynamics of Il1b and Acod1 and performed pathway enrichment analysis to determine the profile of genes co-expressed with Acod1. Early Acod1 upregulation followed by later Il1b downregulation was noted, indicating a shift towards an anti-inflammatory response. Among the genes co-expressed with Acod1, Ldlr, Hadh, and Src are closely associated with lipid metabolism and the polarization of macrophages towards the M2 phenotype, thereby creating a favorable environment for the survival of Leishmania. Overall, these findings suggest that Acod1 and its co-expressed genes may affect the outcome of Leishmania infection by modulating host metabolism. Accordingly, targeting itaconate-associated pathways could provide a novel therapeutic strategy for leishmaniasis.

Keywords: Acod1; Hadh; IL1b; Ldlr; Leishmania; M1/M2 macrophages; Src; itaconate.

Figure 1

Acod1 and Il1b gene expression levels from GSE31995 dataset. (A) Expression counts of infected and non-infected BMDMs at 0 h, 1 h, 3 h, and 6 h. (B) Visualization of kinetics of expression of both genes at the three timepoints. ns, not significant; *** p-value < 0.001; ** p-value < 0.01; * p-value ≤ 0.05.

Figure 2

Volcano plot of genes co-expressed with Acod1 gene expression upregulation (pink dots represent positively correlated genes, blue dots represent negatively correlated genes and grey dots indicate genes that do not show significant correlation. Yellow dashed lines represent thresholds for logFC and −log10 (p-value).

Figure 3

Enriched pathway visualization using EnrichR combined scores.

Figure 4

Cytoscape network visualization of enriched pathways and associate gene sets. Red nodes represent genes co-expressed with Acod1 or their associated pathway, while edges (lines) indicate interactions or associations between them.