Visceral leishmaniasis is not merely a localized skin infection; it attacks the spleen, liver and bone marrow, and it is fatal if untreated. Clinicians have long observed a curious metabolic signature in patients with active disease: elevated triglycerides and very low-density lipoprotein (VLDL), reduced high-density lipoprotein (HDL), and gene polymorphisms linked to lipid handling that appear to act as risk factors for developing overt illness. These observations suggested that lipids are not a side note in leishmaniasis but central players. What remained unknown was exactly which lipid classes change inside infected cells, when those changes occur, and whether they reflect parasite theft, host defense, or both. The new study set out to answer those questions at the level of individual molecular species.

The researchers infected human THP-1 macrophages, a standard model for the immune cells that harbor Leishmania in the body, and performed untargeted lipidomic profiling at two time points after infection. This approach allowed them to compare infected macrophages with uninfected controls and to analyze the intracellular amastigotes, the replicative form of the parasite that lives inside the host cell’s phagolysosomes. By measuring hundreds of lipid species across many structural classes, including phospholipids, sphingolipids, sterols, glycerolipids and fatty acids, the team could build a dynamic picture of how the lipid landscape of the host-parasite unit shifts over the course of infection.

The results were striking. Infection produced an enrichment of sterols, sphingolipids and phospholipids that correlated directly with the presence of L. infantum. The pattern of these changes points to substantial transfer of lipids from the host macrophage into the parasite, where exogenous fatty acids are remodeled into polyunsaturated species. In other words, the parasite does not simply scavenge intact host fats; it takes in raw fatty acid building blocks and reassembles them according to its own biochemical blueprint. This remodeling capacity is significant because polyunsaturated lipids influence membrane fluidity, signaling and stress responses, all of which matter for a parasite adapting to the harsh environment inside a macrophage.

At the same time, the host cell paid a heavy price. The infected macrophages showed depletion of mitochondrial lipids, including cardiolipin, the signature phospholipid of the inner mitochondrial membrane, as well as loss of glycosphingolipids. Cardiolipin is essential for oxidative phosphorylation and mitochondrial architecture, so its depletion suggests that the parasite’s lipid demands may compromise the energy machinery of the host cell. Glycosphingolipids, meanwhile, participate in membrane organization, cell signaling and immune recognition, and their loss could contribute to the immune evasion strategies for which Leishmania is well known. The study thus links the parasite’s appetite for fat to concrete, measurable damage in the host cell’s structural and functional lipid inventory.

One of the most intriguing findings is the biphasic nature of the lipid response. In the early phase, lipid metabolism appears geared toward the synthesis of amastigote biomass, supplying the membranes and storage molecules the parasite needs to grow and divide. Later, after the proliferative phase, the profile shifts toward accumulation of post-proliferative lipid storage, with lipids being stockpiled rather than immediately consumed. This two-stage program resembles a metabolic strategy seen in other intracellular pathogens: first exploit the host’s resources for expansion, then consolidate surplus into storage forms that can buffer the parasite against nutrient fluctuations. The timing of these phases, captured at two distinct time points, provides a temporal framework that earlier static snapshots of infection could not offer.

The technical depth of the lipidomic analysis is what makes these conclusions possible. Untargeted lipidomics does not presuppose which molecules matter; instead it surveys the lipidome broadly, detecting species ranging from lysophospholipids and diacylglycerols to cholesteryl esters, ceramides, plasmenyl phospholipids and coenzyme Q species. The authors were able to distinguish, for example, ceramides with short versus long N-acyl chains, and to track parasite-specific sterols such as ergosterol and its esters, which have no mammalian equivalent. That distinction matters: because Leishmania synthesizes ergostane-type sterols rather than cholesterol, the appearance and dynamics of these molecules serve as a molecular fingerprint of parasite lipid metabolism within the infected cell, cleanly separating parasite-driven changes from host responses.

The findings also connect the cellular picture to the clinical one. Patients with active visceral leishmaniasis show dyslipidemia, and the new data suggest a plausible mechanism: the parasite’s systematic extraction and remodeling of host lipids inside macrophages could ripple outward into systemic lipid disturbances. Furthermore, lipid-related gene polymorphisms identified as risk factors for overt disease may act by shaping how much lipid material is available to the parasite or how effectively host cells resist its manipulation. In this view, the outcome of infection depends partly on a metabolic tug-of-war, in which host lipid genetics and parasite lipid appetite together determine whether infection remains contained or blossoms into full disease.

Therapeutically, the study opens several doors. Lipid pathways that the parasite depends on but that differ from human biochemistry, such as ergosterol synthesis and the remodeling of scavenged fatty acids into polyunsaturated species, are attractive drug targets. Existing antifungal drugs exploit precisely this kind of sterol difference, and the new data map in detail which lipid classes accumulate or collapse during infection, offering a molecular checklist for interventions that could starve the parasite or protect host mitochondrial function. The biphasic pattern also carries a caution: any metabolic therapy would need to account for the stage of infection, since the parasite’s lipid requirements change as it shifts from proliferation to storage.

As a contribution to basic science, the work deepens the understanding of lipids’ central role in parasite growth and disease progression, an area that has lagged behind studies of genomes and proteins. It demonstrates that Leishmania infantum infection is not a passive coexistence but an active metabolic occupation, in which the parasite commandeers the host cell’s lipid economy with remarkable specificity and timing. For a disease that affects hundreds of thousands of people each year and remains one of the most neglected of the neglected tropical diseases, such mechanistic insight is a valuable step toward new strategies, whether drugs that block lipid transfer, biomarkers that track metabolic stages of infection, or a fuller explanation of why some patients’ lipid genetics leave them vulnerable. The parasite, it turns out, is truly hooked on fat, and understanding that addiction may be the key to breaking it.

Subject of Research: Host lipid manipulation by the protozoan parasite Leishmania infantum during macrophage infection

Article Title: Hooked on fat: host lipid manipulation by protozoan Leishmania infantum

Article References: Siess-Portugal, C., Chaves-Filho, A. B., Ozaki, C. Y., Ramos-Sanchez, E. M., Reis, L. C., Miyamoto, S., Yoshinaga, M. Y., & Goto, H. (2026). Hooked on fat: host lipid manipulation by protozoan Leishmania infantum. Parasites & Vectors. https://doi.org/10.1186/s13071-026-07691-9

Image Credits: AI Generated

DOI: 10.1186/s13071-026-07691-9

Keywords: Leishmania infantum, visceral leishmaniasis, lipidomics, host-parasite interaction, macrophages, lipid metabolism, sphingolipids, cholesterol trafficking, intracellular amastigotes, immune evasion, parasite physiology, neglected tropical diseases