Leishmania infantum triggers lipid peroxidation and non-canonical cell death in macrophages
Year: 2026
Type: article
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.
Source: Frontiers in Immunology
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
Awards: INNATE-GAP: a next-generation humanized mouse model for closing the translational gap in innate immunity research, G1596266482, Molecular basis for infection and quiescence of Leishmania in the bone marrow, Blocking ischemia reperfusion injury during dynamic preservation of organ grafts using lead ferroptosis inhibitors, G3499316158, G5951548059, G6072363096, Investigating the cell type specific mechanisms by which Gasdermin D-mediated cell death provokes Nlrp3 inflammasome driven inflammation, Novel mechanisms of inflammation and cell death regulation in autoinflammatory and infectious diseases, Dissecting cellular interactions underlying auto-inflammation in Familial Mediterranean Fever., Host-microbe interaction in intestinal homeostasis: unravelling the mechanisms involved in the onset of multiple inflammation-related diseases, Characterizing how excessive linear ubiquitination in myeloid cells modulates inflammasome responses as well as host defence against inflammasome-activating pathogens., G9001302820, G9001302893
OpenAlex ID: W7221955004