Leishmania infantum triggers lipid peroxidation and non-canonical cell death in macrophages
5 affiliations
- 1Cell Death Signaling Laboratory, Infla-Med Centre of Excellence, Department of Biomedical Sciences, University of Antwerp
- 2Laboratory of Microbiology, Parasitology and Hygiene, Infla-Med Centre of Excellence, Department of Biomedical Sciences, University of Antwerp
- 3VIB Center for Inflammation Research, VIB
- 4Department of Biomedical Molecular Biology, Ghent University
- 5Department of Internal Medicine and Pediatrics, Ghent University
Abstract
Leishmania infantum is a causative agent of visceral leishmaniasis and survives as an obligate intracellular parasite within macrophages by modulating host cell death pathways. While preservation of host cell viability is critical for parasite replication, infected macrophages ultimately undergo cell death, although the mechanisms remain unclear. Here, we investigated the nature of L. infantum -induced cell death in murine bone marrow-derived macrophages (BMDMs). Using long-term live-cell imaging, we show that L. infantum induces delayed cell death in lipopolysaccharide (LPS)-primed macrophages. This process occurred independently of Gasdermin D (GSDMD) and was not associated with inflammasome activation, as evidenced by the absence of caspase-1 cleavage and IL-1β secretion. Consistently, GSDMD deficiency did not affect visceral parasite burden or systemic inflammation during L. infantum infections in mice. Combined genetic ablation of key mediators of apoptosis (caspase-8), necroptosis (RIPK3), and inflammasome signaling (caspase-1/11) failed to protect macrophages from L. infantum -induced cell death, indicating that classical lytic and apoptotic pathways were dispensable. Instead, L. infantum -induced non-canonical macrophage death was associated with robust lipid peroxidation, a hallmark of ferroptosis. However, pharmacological inhibition of lipid peroxidation using ferrostatin-1 did not rescue cell viability, while genetic ablation of the anti-ferroptotic enzyme GPX4 enhanced lipid peroxidation without further sensitizing infected macrophages to death. These findings suggest that L. infantum is capable of uncoupling lipid peroxidation from cell death in macrophages. Together, our results reveal that L. infantum induces lipid peroxidation without triggering ferroptosis and instead drives a non-canonical form of macrophage death independent of major known pathways.
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BibTeX
@article{mortelmans2026leishmania,
title = {{Leishmania infantum triggers lipid peroxidation and non-canonical cell death in macrophages}},
author = {Silke Mortelmans and Bregje Christiaenssen and Sarah Hendrickx and Geert van Loo and Tom Vanden Berghe and Guy Caljon and Andy Wullaert},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1891865},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1891865/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Leishmania infantum triggers lipid peroxidation and non-canonical cell death in macrophages
AU - Silke Mortelmans
AU - Bregje Christiaenssen
AU - Sarah Hendrickx
AU - Geert van Loo
AU - Tom Vanden Berghe
AU - Guy Caljon
AU - Andy Wullaert
PY - 2026
DA - 2026/10/15
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1891865
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1891865/full
AB - Leishmania infantum is a causative agent of visceral leishmaniasis and survives as an obligate intracellular parasite within macrophages by modulating host cell death pathways. While preservation of host cell viability is critical for parasite replication, infected macrophages ultimately undergo cell death, although the mechanisms remain unclear. Here, we investigated the nature of L. infantum -induced cell death in murine bone marrow-derived macrophages (BMDMs). Using long-term live-cell imaging, we show that L. infantum induces delayed cell death in lipopolysaccharide (LPS)-primed macrophages. This process occurred independently of Gasdermin D (GSDMD) and was not associated with inflammasome activation, as evidenced by the absence of caspase-1 cleavage and IL-1β secretion. Consistently, GSDMD deficiency did not affect visceral parasite burden or systemic inflammation during L. infantum infections in mice. Combined genetic ablation of key mediators of apoptosis (caspase-8), necroptosis (RIPK3), and inflammasome signaling (caspase-1/11) failed to protect macrophages from L. infantum -induced cell death, indicating that classical lytic and apoptotic pathways were dispensable. Instead, L. infantum -induced non-canonical macrophage death was associated with robust lipid peroxidation, a hallmark of ferroptosis. However, pharmacological inhibition of lipid peroxidation using ferrostatin-1 did not rescue cell viability, while genetic ablation of the anti-ferroptotic enzyme GPX4 enhanced lipid peroxidation without further sensitizing infected macrophages to death. These findings suggest that L. infantum is capable of uncoupling lipid peroxidation from cell death in macrophages. Together, our results reveal that L. infantum induces lipid peroxidation without triggering ferroptosis and instead drives a non-canonical form of macrophage death independent of major known pathways.
SN - 1664-3224
ER -