Differential expression of polyamine biosynthetic pathways in skin lesions and in plasma reveals distinct profiles in diffuse cutaneous leishmaniasis

Abstract

to be linked to the parasite load in lesion sites 3. In MCL lesions, parasites are rarely detected whereas in DCL lesions heavily parasitized macrophages are usually observed 2. We have previously shown high concentrations of arginase-1 (ARG1), ornithine decarboxylase (ODC), prostaglandin E2 (PGE2) and transforming growth factor β (TGF-β) in DCL patients 4 , which could contribute to an ineffective immune response unable to hamper parasite replication. Although recent studies have shown that components of the polyamine biosynthetic pathway are linked to survival of Leishmania sp. inside macrophages in experimental settings 5,6 it is unknown whether there is a differential expression of such components in patients with distinct clinical forms of TL. Among the metabolites from the polyamine pathway, putrescine, cadaverin, spermidine and spermine are aliphatic cations derived from amino acids such as l-arginine and lysine, with multiple functions which are essential for all living organisms 7. Polyamines are critically involved in a diverse range of cellular processes such as regulation of gene expression and translation, modulation of cell signaling, membrane stabilization and cell proliferation 7,8. These metabolites are synthesized in a reaction catalyzed by ARG1, which converts l-arginine to l-ornithine and urea 6. Another enzyme, ODC, catalyzes l-ornithine conversion to putrescine 6. Putrescine then participates in an intricate cascade of reactions involving several enzymes such as spermidine synthase (SpdS) and spermine synthase (SpmS), which results in formation of polyamines, spermidine and spermine, respectively 6. Cadaverine, a polyamine poorly studied in humans, is derived from the amino acid lysine 9. The uptake of l-arginine in macrophages infected with Leishmania sp. occurs via transporters from the cationic amino acid family (CAT) 10. Hence, inhibition of the l-arginine transporter by melatonin reduces parasite burden by decreasing the production of polyamines 11. We have previously demonstrated that treatment of L. amazonensis infected macrophages with arginase or ODC inhibitors leads to enhanced parasite clearance and dampened secretion of pro-inflammatory cytokines 4. Indeed, different immune response profiles can influence l-arginine catabolism that, ultimately, result in resistance or susceptibility to Leishmania infection. l-arginine is catabolized by ARG1 in the presence of interleukin 4 (IL-4), IL-10, IL-13 and TGF-β, producing polyamines and collagen and enhancing Leishmania infection 12. In converse, in the presence of pro-inflammatory mediators, such as interferon γ (IFNγ), tumor necrosis factor α (TNFα) and IL-12, the nitric oxide synthase 2 (iNOS/NOS2) will be preferentially activated, resulting in production of nitric oxide (NO) and citrulline 12,13. Although NO alone is not sufficient to control infection, it can be further metabolized in reactive nitrogen and oxygen species, which are then involved in parasite killing 14,15. Therefore, the profile of the host immune responses dictates ...

Metabolomic Reprogramming of C57BL/6-Macrophages during Early Infection with L. amazonensis

“…Clinical data of diffused cutaneous leishmaniasis (DCL) showed that patients present higher ornithine, spermidine, and citrulline in plasma samples than mucocutaneous leishmaniasis (MCL), using HPLC tool [49]. Indeed, DCL skin biopsies upregulated arginase 1 (ARG1) and spermine synthase mRNAs involved in polyamines biosynthesis concerning localized cutaneous leishmaniasis (LC) and MCL lesions, highlighting the significance of host ARG1 and arginine transporter (cationic amino acid transporter, CAT2) in MCL [49]. However, the ARG1 and arginase 2 (ARG2) transcripts are lower in DCL than healthy controls [49].…”

“…Indeed, DCL skin biopsies upregulated arginase 1 (ARG1) and spermine synthase mRNAs involved in polyamines biosynthesis concerning localized cutaneous leishmaniasis (LC) and MCL lesions, highlighting the significance of host ARG1 and arginine transporter (cationic amino acid transporter, CAT2) in MCL [49]. However, the ARG1 and arginase 2 (ARG2) transcripts are lower in DCL than healthy controls [49]. L. amazonensis infection of BALB/c-macrophages increases host Cat2 and Arg1 transcripts, parasite arginine transporter (amino acid permease 3, AAP3), and parasite arginase [23].…”

Arginine-mediated gut microbiome remodeling promotes host pulmonary immune defense against nontuberculous mycobacterial infection

“…These observations suggest that l -arginine is preferentially metabolized for the biosynthesis of polyamine pathway intermediates as opposed to the biosynthesis of NO biosynthetic pathway intermediates ( Figure 1c ). 33 , 34 Furthermore, we found no significant differences in the concentration of citrulline, a precursor of l- arginine, between HCs and NTM-PD patients, although a minor but significant increase in arginino-succinate was detected in patients with Mabc infection compared to HCs ( Figure 1b ). These data suggest that l- arginine depletion is a result of rapid consumption rather than reduced biosynthesis.…”

Advances in Understanding Leishmania Pathobiology: What Does RNA-Seq Tell Us?

“…Recently, Malta-Santos et al (2020) investigated the importance of the polyamine biosynthetic pathway in CL lesions. Diffuse CL was associated with higher concentrations of amino acids, polyamines and its substrate transporters compared to MCL or localized CL.…”

“…The most upregulated transcripts in diffuse CL lesions were CAT2A (isoform encoded by SLC7A2), ARG1 and SMS compared to MCL lesions acting in the regulation of arginine availability. A differential gene expression of polyamine metabolism-related genes of patients’ lesions was associated with parasite loads and the leishmaniasis disease outcome ( Malta-Santos et al, 2020 ).…”