Leishmania is critically dependent on L-arginine for survival (13) and possess its own L-arginine metabolic pathway (14, 15). The parasite imports its own L-arginine via the transporters LdAAP3 and CAT-2B (16), with LdAAP3 being highly specialized for arginine uptake under acidic conditions (16, 17). Leishmania also expresses key enzymes involved in L-arginine metabolism, including arginase (ARG), and ornithine decarboxylase (ODC) (13, 18–20). Notably, parasite arginase activity can be enhanced by the host protein, insulin-like development factor-I (IGF-I), thereby promoting parasite growth in macrophages (21). ARG converts L-arginine to L-ornithine, which is subsequently metabolized by ODC to polyamines: putrescine, spermidine and spermine, that are essential for parasite proliferation (19).

Given its importance for parasite survival, the L-arginine metabolic pathway represents a key target of host defense (10). Pharmacological inhibition of arginase, such as using N^ω-hydroxy-l-arginine, leads to a decrease in parasite growth (22). Similarly, treatment of Leishmania-infected macrophages with arginase inhibitor decreases intracellular parasite burden by suppressing both host and parasite arginase activity (23). Likewise, ODC inhibitors, such as D, L-α-difluoro-methyl ornithine (DFMO), and 3-aminooxy-1-aminopropane (APA), restrict parasitic infection (24–26). Together, these findings support the concept that Leishmania has evolved its L-arginine metabolic machinery to compete with the host for this essential nutrient in order to survive and proliferate (10).

Polyamines (PA), including putrescine, spermidine (Spd), and spermine, are produced via the ARG pathway, which is induced in alternatively activated and metabolically suboptimal macrophages (27, 28). These PA support parasite replication and persistence and are essential for trypanothione sysnthesis, a thiol-based antioxidant that protects Leishmania from peroxynitrite-mediated cytotoxicity (29). In the PA biosynthetic pathway, ARG converts L-arginine to L-ornithine, which is then decarboxylated by ODC to produce putrescine. Putrescine subsequently converted to spermidine by spermidine synthase (SpdS), using an aminopropyl group donated by decarboxylated S-adenosylmethionine, generated by S-adenosylmethionine decarboxylase (AdoMetDC) (30). Spermine is produced by the addition of a second aminopropyl group by spermine synthase (31).

Several PA biosynthetic enzymes are essential for Leishmania survival and represent promising novel drug targets. AdoMetDC deficient parasites are unable to grow in PA-depleted conditions, a phenotype rescued by spermidine but not by putrescine or spermine. Consequently, inhibitors of AdoMetDC, such as MDL73811 and CGP 40,215A display potent antileishmanial activity (32, 33). SpdS is also essential for L. donovani amastigotes, as spds^-/- parasites require exogenous spermidine for growth and exhibit reduced infectivity in vivo (31). Notably, pentamidine-resistant parasites adapt by increasing SpdS affinity for putrescine while reducing drug binding, highlighting the role of PA metabolism in drug resistance (33, 34).

Leishmania maintains a redox homeostasis through a unique thiol-based system distinct from its invertebrate and vertebrate hosts. The parasite lacks glutathione reductase (GR) (35, 36) and instead relies on N¹, N⁸-bis(glutathionyl) spermidine (trypanothione) and its precursor, N¹-glutathionyl spermidine, as the principle intracellular thiols. These molecules are recycled by trypanothione reductase (TR), an NADPH-dependent flavoprotein oxidoreductase (35, 37, 38). Although structurally related to GR, TR has distinct substrate specificity, enabling selective pharmacological targeting (37, 39). TR protects Leishmania from oxidative stress and its deficiency markedly attenuates parasite virulence (36, 40, 41). Trypanothione further protects Leishmania by scavenging nitric oxide (NO) and labile iron by forming a di-nitrosyl iron complex (36, 42, 43).

Additionally, tryparedoxin-dependent peroxidases (TPs), which are members of the 2-cysteine peroxiredoxin family, protect Leishmania from hydroperoxides by reducing them to water and alcohol (44–46). TPs have also been implicated in the metastasis of Leishmania guyanensis (47), enhanced infectivity, and reduced parasite responsiveness to antimonial drugs (46).

Ergosterol is essential for maintaining cell membrane integrity of fungi and protozoa, like the role of cholesterol in mammalian cells. Moreover, Leishmania cannot synthesize cholesterol and instead acquires it from the host cell (48). Amphotericin B (Amp-B), a key antileishmanial drug, has high affinity for ergosterol and induces parasite death by forming pores in the plasma membrane leading to its lysis (49). Dynamic changes in sterol composition have been linked to promastigote metacyclogenesis and altered parasite virulence (50).

Sterol alkylation position C24, catalyzed by the enzyme S-adenosyl-L-methionine: C24-Δ-sterol-methyltransferase (SMT), represents the final step of sterol biosynthesis in trypanosomatids. Inhibition of SMT affects parasites survival through sterol depletion leading to morphological defects (51). However, loss of functional SMT has also been associated with Amp-B drug resistance as parasites deficient in SMT lack ergosterol, reducing Amp-B insertion into the parasite membrane (52). Upstream of SMT, C14α-sterol demethylase (14DM) catalyzes demethylation at the C14 position of sterol intermediates and is the primary target of azole drugs, including itraconazole (ITZ) (20, 49). Depletion of 14DM in Leishmania promastigotes results in pronounced morphological and cytokinetic defects, although parasites retain the capacity to proliferate at a reduced growth rate (53).

Glucose is a major carbon and energy source for Leishmania (54). Although both promastigote and amastigote forms utilize glucose, catabolism of this molecule is significantly higher in the promastigotes (55). This reflects the sugar rich microenvironment of the sandfly and glucose-limited phagolysosomes of the macrophages where promastigotes and amastigotes respectively reside (56, 57). Accordingly, amastigotes exhibit reduced glucose uptake and rely predominantly on fatty acid oxidation for energy production (55, 58). In this context, glucose uptake primarily supports the biosynthesis of glycoconjugates, including β-mannan. Genetic ablation of glucose transporters disrupts glycoconjugates biosynthesis and compromises parasite survival (59). In L. mexicana, glucose transporter deficient promastigotes (Δlmgt) display reduced growth rates (60). While Δlmgt amastigotes show severely reduced viability inside macrophages and fail to proliferate as axenic amastigotes, depicting the essential role of glucose transporters in amastigote survival (60).

Under oxidative stress, Leishmania redirects glucose metabolism from glycolysis toward the pentose phosphate pathway to restore NADPH levels. Overexpression of glucose-6-phosphate dehydrogenase (G6PDH) and transaldolase enhances resistance to reactive oxygen species (ROS) and antileishmanial drugs, including sodium antimony gluconate (SAG) (61). Consistently zinc sulfate exhibits direct antileishmanial activity by inhibiting multiple enzymes involved in glucose metabolism, including fructo-phosphokinase, glucose phosphate isomerase, hexokinase, G6PDH, and ribose-5-phosphate isomerase (62). Deletion of Phosphomannomutase (PMM) which catalyzes mannose-6-phosphate to mannose-1-phosphate in L. mexicana, results in loss of virulence, indicating identifying PMM as a promising therapeutic drug target (63).

Leishmania lacks de novo heme biosynthesis and iron/heme storage system. Given the critical role of heme and iron in parasite survival and virulence, Leishmania has evolved efficient scavenging system to obtain these nutrients from the host (64–66). Hemoglobin degradation and heme depletion serves as differentiation cues, driving promastigote maturation from a proliferative, non-infective form to a non-dividing, infective metacyclic stage (67, 68). Amastigotes survive in the parasitophorous vesicle of a macrophage by scavenging host-derived heme and iron (69). Inside the parasitophorous vacoule, iron is primarily present as Fe³⁺ complexed with transferrin and lactoferrin. Leishmania preferentially utilizes Fe²⁺ which is generated through NADPH-dependent reduction of Fe³⁺ by Leishmania ferric reductase 1 (LFR1), which is expressed on parasite membrane (70–72). Uptake of reduced iron is mediated by Leishmania iron transporter 1 (LIT1), an iron-responsive transporter essential for parasite replication and virulence (68, 69) Similarly, Leishmania heme response 1 (LHR1), present in the plasma membrane and endocytic compartment, promotes heme transport to the cytosol and its absence attenuates parasite virulence (73, 74).

Following cytosolic uptake, iron is transported into mitochondria by Leishmania mitoferrin 1 (LMIT1) (75), where enzymes including coproporphyrinogen oxidase, protoporphyrinogen oxidase, and ferrochelatase, contribute to heme biosynthesis from host-derived precursors (66, 76, 77). Iron is also required in glycosomes, where anti-oxidant enzymes such as superoxide dismutase A (SODA) and ascorbate peroxidase (AP) depend on iron cofactors to protect parasites from oxidative stress within the macrophage environment (78, 79).

Macrophages play a dual role in Leishmania infection: they serve as the definitive hosts for parasite proliferation and as effector cells involved in parasite clearance. For parasite clearance, macrophages must be classically activated (M1), resulting in the production of parasiticidal effector molecules. This classical activation requires stimulation by interferon-gamma (IFN-γ), produced primarily by activated CD4⁺ T cells. The binding of IFN-γ to its receptors on macrophages induces the expression of inducible nitric oxide synthase (iNOS), leading to the production of NO. This NO, together with its reactive derivatives, including peroxynitrates, contribute to parasite killing inside infected macrophages (12, 80). Conversely, alternatively activated macrophages (M2), which are favored by Th2 cytokines, including IL-4 and IL-13, promote parasite survival and replication. These cytokines, particularly IL-4, enhance polyamine synthesis by upregulating L-arginine metabolism (12). The macrophage polarization induced by Leishmania infection depends on parasite species and strain. In visceral leishmaniasis, L. donovani infection in humans and L. infantum infection in dogs are associated with M2 macrophage polarization, characterized by increased expression of CD163, IL-10, and CXCL14 (81–83). In contrast, cutaneous leishmaniasis exhibits mixed macrophage responses: L. braziliensis and L. major preferentially induce M1 macrophages, whereas L. amazonensis promotes M2 polarization (84–86). Thus, the activation state of macrophages –M1 or M2 – critically influences the outcome of Leishmania infection, determining whether the parasite is eliminated or allowed to proliferate.

Apart from cytokines, the M1 or M2 activation state of macrophages is also influenced by metabolites in the cells’ microenvironment. Specifically, the levels of host amino acids and the status of central carbon metabolism play significant roles in determining macrophage activation state. Upon stimulation with IFN-γ, macrophages upregulate the cationic amino acid transporter, CAT2B, resulting in increased uptake of L-arginine and increased expression of iNOS (87, 88) (Figure 1A). iNOS in turn catalyzes the conversion of L-arginine to citrulline and NO, a potent parasiticidal molecule. The induction of iNOS and subsequent production of NO inhibits mitochondrial oxidative phosphorylation (OxPhos) (89), compelling macrophages to rely predominantly on glycolysis to meet their energy needs. This glycolytic shift supports the production of ROS, which supports M1 while inhibiting M2 macrophage polarization.

M2 macrophage polarization is driven by IL-4 and IL-13 signals through a heterodimeric receptor complex composed of the IL-4 receptor alpha chain (IL-4Rα) and the IL-13 receptor alpha 1 chain (IL-13Rα1) (90, 91) (Figure 1B). Ligation of the IL-4/IL-13 receptors leads to activation of the JAK/STAT6 signaling pathway, which induces the transcription of M2-associated genes, including CAT2B and Arginase-1 (Arg-1) (92). Arg-1 catalyzes the conversion of L-arginine to ornithine and urea, promoting polyamine synthesis that supports parasite proliferation. Arg-1 and iNOS compete for the same substrate, L-arginine, and their expression is reciprocally regulated by distinct cytokine cues. The upregulation of one enzyme can inhibit the function of the other; for example, Arg-1 inhibits iNOS, and vice versa.

Although host Arg-1 is a potent inhibitor of iNOS, it does not appear to contribute to play a significant role in disease pathogenesis (93). Genetic deletion of Arg-1 in both hematopoietic and non-hematopoietic in C57BL/6 mice had no noticeable effect on lesion development or parasite burden during Leishmania infection (93). Interestingly, pharmacologic inhibition of Arg-1 with nor-NOHA in BALB/c mice delayed disease progression, while ornithine treatment of the resistant C57BL/6 mice resulted in worsening of cutaneous leishmaniasis (94, 95). These findings suggest that both host-derived and parasite-derived Arg-1 activity may contribute to disease outcomes, possibly by increasing arginine metabolism and promoting parasite (95).

Following Leishmania-infection, murine macrophages initially develop a phenotype akin to an M1 state, characterized by elevated glycolysis levels and increased host glucose transporters (Table 1) (96). However, this proinflammatory phenotype is transient, because after 24 hours post-infection, they undergo a significant metabolic and functional shift toward an M2 phenotype, which is characterized by increased reliance on oxidative phosphorylation as studied by the Seahorse assay (96). This M2 polarization is supported by enhanced activity in the tricarboxylic acid (TCA) cycle, fatty acid β-oxidation, and glutaminolysis (Table 1). Additionally, M2 polarized macrophages exhibit increased expression of 3-phosphoglycerate dehydrogenase, which redirects glycolytic intermediates into serine, glycine and folate metabolism (108). The highly efficient OxPhos machinery in M2 macrophages results in elevated glucose levels, which in turn favors high intracellular glucose levels that promote the proliferation of intracellular amastigotes. In contrast, IFN-γ-activated M1 macrophages exhibit a metabolically rewired state that favors highly inflammatory glycolytic pathway. The internalized glucose is predominantly metabolized via the pentose phosphate pathway (PPP), generating NADPH and ATP, which are essential for the production of ROS. Although pyruvate is still produced, its entry into the TCA cycle is impaired, resulting in the accumulation of metabolites such as citrate, isocitrate and succinate in the cells. These intermediates promote β-oxidation of fatty acids and activate the transcription factor, HIF1α. HIF1α in turn promotes the induction of glycolytic enzymes and inflammatory cytokines, such as IL-1β, thereby reinforcing the microbicidal activity of M1 macrophages and contributing to parasite destruction (108).

The mammalian target of rapamycin (mTOR) is a major regulator of carbon metabolism in eukaryotic cells. There are two functional types of mTOR complexes expressed in immune cells: mTOR complex 1 (mTORC1) and mTORC2, which differ in their affinities for rapamycin and are largely independent. mTORC1 has been linked to the regulation of Leishmania-infected macrophage polarization. Specifically, M2 polarization is promoted via mTORC1 activation following the ligation of IL4/IL13 receptors on macrophages. Engagement of these receptors activates the PI3K/protein kinase B (Akt) pathway, which in turn activates mTORC1. Activated mTORC1 in turn promotes transcription and translation of metabolic enzymes necessary to mediate the synthesis of metabolites favorable to parasite proliferation (109). In support of this, inhibition of mTORC1 in mice infected with L. donovani reduced parasite numbers in ex vivo macrophages and granuloma formation in the liver (110). Additionally, mTORC1 activation upregulates the expression of enzymes involved in fatty acid synthesis and lipid body formation, resulting in elevated lipid and triglyceride levels in splenic and hepatic macrophages from L. donovani-infected mice, as assessed by real time PCR and high performance thin layer chromatography (111). Notably, mTORC1 also promotes the expression of HIF1α, a key transcription factor that supports metabolic reprogramming in cells. L. donovani infection downregulates HIF1α expression and this was associated with an increased number of amastigotes in macrophages (111). Interestingly, HIF1α appears to have a dual role in regulating macrophage M1 and M2 polarization. In M1 macrophages, succinate accumulation stabilizes HIF1α, promoting proinflammatory gene expression, leading to parasite killing. The exact mechanism by which the same transcription factor mediates M2 and M1 polarization is not fully understood. Still, it has been suggested that mTORC1 activation occurs through proteolytic cleavage mediated by parasite-derived metalloprotease, gp63. The inhibition of mTORC1 in L. major-infected macrophages has been shown to induce type 1 interferon response, resulting in M1 polarization and impairment in the OxPhos system. This metabolic reprograming leads to the production and accumulation of TCA cycle intermediates such as citrate, itaconate and succinate, which subsequently activate and stabilize HIF1α and reinforce the inflammatory parasiticidal state (112, 113).

Bioinformatic and immunofluorescence studies have shown that lipid bodies are formed in the cytoplasm of murine and human macrophages during Leishmania infection and are commonly found around the parasitophorous vacuole (114, 115). They serve as an alternative carbon source for Leishmania amastigotes and as a stable source of polyunsaturated fatty acids. In addition to fueling parasite metabolism, lipid bodies also protect the parasites against oxidative stress (116), thereby promoting parasite survival. Importantly, lipid bodies contribute to the establishment of the M2 macrophage phenotype during Leishmania infection by serving as precursors for lipid mediators that regulate both inflammatory and anti-inflammatory activities through omega-3 and omega-6 pathways (Table 1). For instance, the level of prostaglandin E2 (PGE2), a potent anti-inflammatory lipid molecule that dampens Th1 responses and promotes M2 polarization, is increased in L. donovani-infected macrophages (97). PGE2 acts in part via activation of the peroxisome proliferator-activated receptor gamma (PPAR-γ), which a master regulator of lipid metabolism that acts upstream of mTORC1. PPAR-γ activation promotes the expression of genes associated with OxPhos and Arg-1 enzyme, both of which are characteristic of M2 macrophage phenotype (117). In line with this, activation of PPAR-γ in both cutaneous and visceral leishmaniasis has been associated with progressive disease, while its inhibition of genetic disruption leads to reduced parasite burdens in infected macrophages (117, 118). PPAR-γ expression can be induced by anti-inflammatory cytokines such as IL-4, IL-10, IL-13 as well as various lipid ligands, including polyunsaturated fatty acid (PUFA) and prostaglandin E. Indeed, Leishmania-derived PUFA has been shown to directly influence the polarization of macrophages toward the M2 phenotype (119). Collectively, these findings show how Leishmania employs multiple mechanisms to strategically manipulate various metabolic pathways, particularly through lipid body formation, PPAR-γ activation, and mTORC1 signaling, to favor M2 macrophage polarization and support parasite survival and replication.

Neutrophils are among the first immune cells recruited to sites of Leishmania infection and play a complex role in disease pathogenesis (120–122). Leishmania has evolved strategies to evade destruction by neutrophils including altering their metabolism to enhance its own survival. During their development and activation, neutrophils adapt to diverse and often harsh environments that are characterized by hypoxia and nutrient deficiency. This involves a metabolic reprogramming, transitioning from the bone marrow to a more activated states under disease conditions (98). Inflammation leads to recruitment of metabolically active immune cells resulting in localized hypoxia and reduced nutrient availability (123). Despite this, neutrophils retain functionality through metabolic adaptations that rely on glycolysis to supply over 90% of their ATP, independent of oxygen availability. This adaptation is augmented by activation of the transcription factor hypoxia-inducible factor (HIF-1α) which supports rapid ATP generation under hypoxic conditions (Figure 2). Under steady-state conditions, neutrophils primarily utilize glycolysis to generate ATP, and this is supported by high levels of oxygen, glucose, and glutamine present in plasma, bone marrow, and peripheral tissues (98). They also maintain a balanced redox state through the pentose phosphate pathway to produce NADPH, which is crucial for generating ROS for antimicrobial functions. This basal metabolic profile allows neutrophils to remain poised for activation without undergoing excessive and premature effector responses (124). Upon encountering inflammatory stimuli, neutrophils rapidly shift their metabolic profile to meet their increased energetic and biosynthetic demands. This includes increased glycolysis, enhanced PPP activity, and possibly increased fatty acid oxidation (FAO) (125). Collectively, these metabolic adaptations allow neutrophils to function efficiently in the diverse tissue environments.

Upon encountering L. donovani parasites, neutrophils undergo a metabolic shift characterized by increased glycolytic activity as measured by Seahorse analysis. This promotes the use of glucose to generate energy needed for its rapid response including phagocytosis, production of ROS, and release of inflammatory mediators (99). This allows neutrophils to combat the parasites at the site of infection, highlighting the crucial role of glucose metabolism in neutrophil-mediated immunity. Interestingly, inhibiting glycolysis negatively impacts the metabolic machinery of both Leishmania promastigotes and neutrophils, underscoring the dependency of both cells on glycolysis. Notably, no increase in ATP production from OxPhos was observed in L. donovani-infected neutrophils, further validating glycolysis as the dominant energy source in this context (99).

Under steady state condition, the uptake of glucose by neutrophils occurs primarily through the glucose transporter GLUT1 (126). Following activation, additional transporters, GLUT3 and GLUT4 are upregulated, ensuring sufficient glucose supply to meet the increased metabolic demands (127). Once internalized, glucose is rapidly phosphorylated to glucose-6-phosphate (G6P), preventing it from exiting the cell. G6P is then transported into the endoplasmic reticulum via the G6P transporter, where it can be converted back into glucose (98). This process is critical for restricting glucose metabolism fluxes in physiologic conditions, preserving energy metabolism for active inflammation.

The metabolic outcome of G6P (glycolysis or pentophosphate pathway) in neutrophils is influenced by their activation state. Glycolysis leads to the production of pyruvic acid, which, under aerobic conditions, can be further oxidized in the mitochondria via the TCA cycle (Table 1). However, liquid chromatography–mass spectrometry (LC–MS) and metabolic flux analyses reveal that, in activated neutrophils, pyruvate is predominantly diverted to lactate production, which is critical for sustaining glycolytic flux. Additionally, G6P in neutrophils also fuels the pentose phosphate pathway (PPP) metabolic process that generates NADPH which is essential for ROS-production (98, 128). Under homeostatic states, glutamine metabolism supports the basal synthesis of purines and nucleotides and contributes to the production of glutamate, aspartate, and lactate. However, during pathophysiological conditions characterized by reduced glucose levels, neutrophils increasingly rely on glutamine metabolism, which shift enhances NADPH production and NOX function (129). Despite reliance on glycolysis for energy, neutrophils still retain functional mitochondrial. The extent to which neutrophils retain mitochondrial metabolism remains understudied. Current evidence suggests that glucose-derived acetyl CoA plays a minimal role in mitochondrial ATP generation, while fatty acid-derived CoA may serve as an alternative substrate (130).

In neutrophils, mTOR functions as a central regulator of metabolic activity during inflammatory conditions. Loss of mTOR in activated neutrophils limits their ability to migrate, differentiate, and eliminate pathogens through the formation of neutrophil extracellular traps (NETs) (131, 132). Evidence suggests that Leishmania may modulate mTOR in neutrophils, thereby delaying or suppressing the execution of neutrophil effector functions. Additionally, hypoxia-inducible factor 1-alpha (HIF1α) is critical for neutrophil antimicrobial activity and survival; and its absence significantly reduces both functions (133). Another important metabolic regulator, peroxisome proliferator-activated receptor gamma (PPARγ), appears to influence effector function of neutrophils. In models of sepsis, elevated PPARγ levels appear to influence neutrophil chemotactic activity, and this effect could be reversed with the administration of a PPAR antagonist (134). Collectively, these findings suggest that Leishmania may impair neutrophil activation and oxidative effector functions by modulating key pathways of glucose metabolism. Further investigation is needed to fully understand how different Leishmania species modulate the activity of key metabolic enzymes in neutrophils.

DCs serve as a critical bridge between the innate and adaptive immunity. In leishmaniasis, DC indirectly influence macrophage polarization and parasite killing by enhancing Th1 polarization leading to IFN-γ production necessary for parasite killing (12). However, it is believed that Leishmania modulates DCs to subvert their functions and hence evade immune clearance.

DC immunometabolism is central to their effector activity. Under homeostatic conditions, DCs rely on oxidative phosphorylation (OxPhos) and fatty acid oxidation (FAO), whereas inflammation drives a shift in their metabolism toward aerobic glycolysis, which is vital for initiating inflammatory responses (135). Upon TLR ligations DCs significantly increase their glucose uptake and lactate production (101). Early after activation, pyruvate from glycolysis powers the TCA cycle and OxPhos to generate ATP (136). However, around 12 hours post-activation, NO production suppresses OxPhos, forcing reliance on glycolysis for ATP (137). Because glycolysis yields limited ATP, activated DCs engage in complementary pathways as fatty acid synthesis (FAS) and the pentose phosphate pathway (PPP) to support biosynthetic demands (101). Transcriptional profiling indicates that energy production in DCs containing glutaraldehyde-fixed Leishmania depends on TCA cycle and OxPhos. The parasite might also modulate host lipid metabolism by increasing cholesterol uptake while suppressing efflux, leading to cholesterol accumulation within infected DC (Figure 3) (138).

The inflammatory environment is usually hypoxic, which triggers the upregulation and stabilization of HIF1α promoting transcription of glycolytic enzymes (139). Interestingly, mTOR dependent HIF1α activation is independent of glucose availability and sustains DC activation following TLR ligation (101, 140). In visceral leishmaniasis, elevated HIF1α expression in splenic DCs correlates with reduced IL-12 production and impaired Th1 cell expansion (102). Although HIF1α promotes increased glycolytic flux (Table 1), it does not necessarily optimize DC effector function. mTORC1 also supports DC differentiation, and its inhibition leads to a reduction in DCs numbers and IL-12 production, thereby weakening the Th1 immune response (141, 142).

Overall, the suboptimal effector activity of DCs during Leishmania infection may reflect parasite-driven modulation of mTORC signaling. Although the role of DC immunometabolism in Leishmania infection is just starting to be defined, elucidating these pathways will be key to fully understanding and restoring DC-mediated immunity during infection.

During Leishmania infection, in addition to classical Th1 and Th2 cells, other CD4⁺ T helper cell subtypes, such as Th9, Th17, T-regulatory cells (Tregs), and T follicular helper cells (Tfh), can also be induced (143). Th1 cells secrete IFN-γ, which activates infected macrophages to produce ROS and NO, promoting intracellular parasite clearance. Conversely, Th2 cells produce IL-4, IL-5 and IL-13 which drive alternative macrophage activation, increase arginase activity, and promote parasite survival (80). Here, we focus on metabolic reprogramming in T helper cells and Tregs, emphasis on how their interactions with DCs influence their effector functions.

Quiescent naïve T cells, recently matured in the thymus following clonal selection, primarily rely on OxPhos to meet energy demands, occasionally supplementing with glycolysis during intermediate stages after T cell receptor (TCR) rearrangements (Table 1) (103). Upon encountering antigen via TCR-MHC engagement and costimulatory molecules in peripheral tissues, naïve T cells undergo significant metabolic reprogramming, shifting toward aerobic glycolysis while maintaining sine pyruvate flux into the TCA cycle to generated biosynthetic intermediates for lipid or nucleotide synthesis (144). This anabolic shift supports the high metabolic demands of cell growth, proliferation and effector function. For example, glycolytic intermediates such as G6P and 3-phosphoglycerate can be diverted to the PPP and serine synthesis pathway, facilitating nucleotides and amino acids synthesis that is critical for continuous cell activation (145). Elevated glycolytic activity in activated CD4⁺T cells drives the proliferation and differentiation of multiple effector T cell subtypes, including Th1, Th2, Tfh, Treg and Th17 cells.

In Leishmania infection, a hallmark B cell response is the induction of hypergammaglobulinemia. This is driven by B cells polyclonal activation, resulting in the production of large amounts of low-affinity anti-Leishmania antibodies and the formation of multiple immune complexes (161). Depending on the experimental model and/or parasite strain, B cells can play either protective or pathogenic roles in Leishmania infection (162–164).

Prior to antigen encounter and CD40-B-cell activating factor (BAFF) interactions, naïve B cells exhibit high glycolytic capacity and increased basal mitochondrial respiration (165). Antigen encounter through ligation of B cell receptor (BCRs) and/or CD40-IL-4 signaling triggers robust proliferation, protein synthesis and metabolic reprogramming (166). Activated B cells show enhanced glucose uptake via increased GLUT1 expression, leading to increased glycolytic activity, and partial diversion of the flux to the PPP pathway to generate NADPH (Table 1) (107). Concurrently there is upregulation of glycolytic enzymes and amino acid-metabolizing enzymes such as ornithine and phosphoserine aminotransferases, with peak expression observed at 3 days post-activation by Real Time PCR analysis. Increased amino acid uptake supports elevated alanine and glutamate production (167), while glycolytic flux into the hexosamine pathway facilitates antibody glycosylation in plasma cells as assessed by Seahorse analysis (168). Antibody synthesis in plasma cells imposes a high folding and unfolding load in the ER, generating stress responses and ROS. However, this oxidative stress responses are mitigated by increased glycolytic activity and PPP shunt (169). Immunometabolic regulation of activated B cell occurs through HIF1α, Gsk3, Myc and the TRAF3-NF-kB pathways (170). Although the precise mechanism of Leishmania-induced polyclonal activation of B cells remains unclear, parasite proteins LmSIR2 and LmS3a have been implicated in driving B cell glycolysis under inflammatory conditions (171).

The phagolysosome, the intracellular niche for Leishmania, is a nutrient-limited environment in which host and the parasite compete for essential nutrients. During infection, macrophages restrict nutrient availability, forcing the parasite to scavenge for essential nutrients by expressing specialized sensors and transporters (207). This process, broadly termed nutritional immunity, is best illustrated by arginine metabolism. Because arginine is a substrate for both the host iNOS and arginase, competition for this amino acid represents a tug-of-war. Increased arginine flux through iNOS, depletes. Intracellular arginine, thereby limiting parasite proliferation (208). In response, the parasites sense arginine scarcity through mitogen-activated protein kinase 2 (MAPK)-mediated arginine deprivation response, enabling uptake of residual arginine within the phagolysosome (209, 210).

Aside from arginine, Leishmania is auxotrophic for several amino acids and carbon sources. Under nutrient limiting conditions, parasites enter a metabolically quiescent “stringent response”, characterized by reduced growth rate and metabolic reprogramming to ensure maximal utilization of scarce nutrients (211) through expression of parasite-specific transporters or sensors (212).

Iron is a critical micronutrient for antioxidant defense, electron transport and DNA synthesis. Leishmania lacks de novo iron synthesis and storage capacity and thus relies on scavenging iron from the host (64). Within the parasitophorous vacuole (PV), iron availability is tightly regulated by natural resistance-associated macrophage protein-1 (NRAMP-1), which restrict microbial access to iron by exporting it from the compartment (213). To compete for scarce iron, Leishmania employs specialized uptake systems, including ferric iron reductase (LFR1), ferrous iron transporter (LIT1) and the heme transporter1 (LHR1). LFR1 reduces Fe³⁺ to Fe²⁺, enabling LIT1-mediated cytosolic iron import, LHR1 facilitates heme acquisition from host hemoglobin to replenish parasite heme pools (64, 214). Although host iron homeostasis is normally regulated by ferritin and ferroportin, Leishmania can manipulate these pathways to increase iron availability. For instance, L. amazonensis infection promotes hepdidin-mediated degradation of ferroportin, thus limiting iron export from macrophage and increasing intracellular iron accessible to the parasite to siphon (214). This Ferroportin-hepcidin degradation pathway has been shown to increase parasite burden during infection (215). In addition to iron, Leishmania can exploit other host metal ions, including such Zn²⁺, Mg²⁺, Mn²⁺ and Ca²⁺, through dedicated transporters and sensors, especially when these ions are abundant in the parasite microenvironment (212).

Leishmania species exhibit distinct metabolic programs, especially in amino acid metabolism, which critically influence host modulation and nutrient competition. A global mass spectrometry–based metabolomic study of L. major, L. mexicana, and L. donovani cultured under standardized in vitro conditions, revealed significant species-specific metabolic differences independent of environmental factors (216, 217). Notably, L. major depleted nearly all available tryptophan, whereas L. donovani and L. mexicana consumed half and two-thirds, respectively (217). An enhanced parasite-mediated tryptophan depletion may impair host immunity, as reduced tryptophan availability suppresses T cell proliferation and function (218). In addition, L. mexicana exhibited high arginine consumption, while L. major and L. donovani preferentially catabolized arginine to arginic acid (217). Increased arginine flux during infection may favor polyamine synthesis, thus limiting nitric oxide-dependent killing. Together, these intrinsic, species-specific metabolic programs shape host immune response and disease outcomes during Leishmania infection.