Polyamine-Enriched Exosomes from <i>Leishmania\ndonovani</i> Drive Host Macrophage Polarization via Immunometabolism\nReprogramming

Leishmania donovani (<i>Ld</i>) promastigotes\nsecrete exosomes that are crucial in host–pathogen\ninteractions and intercellular communication by carrying parasite-specific\nmolecules. Although the composition of cargos in <i>Leishmania</i> exosomes is known, the effects of the unique metabolic repertoire\non immunometabolism rewiring of macrophage polarization are poorly\nunderstood. Interestingly, we found the enrichment of polyamines (PAs)\nsuch as spermidine and putrescine in the <i>Ld</i>-exosomes.\nHerein, we investigate the critical polycationic molecules and their\ncrucial role in parasite survival. Our study shows that PA inhibition\nor depletion significantly impairs parasite growth and fitness, particularly\nin drug-resistant strains. Furthermore, we aimed to elucidate the\nimpact of PAs-enriched <i>Ld</i>-exosomes on host macrophages.\nThe data demonstrated that macrophages efficiently internalized these\nexosomes, leading to heightened phagocytic activity and infectivity.\nIn addition, internalized <i>Ld</i>-exosomes induced M2\nmacrophage polarization characterized by elevated Arginase-1 expression\nand activity. The increased expression of the solute carrier gene\n(SLC3A2) and elevated intracellular spermidine levels suggest that <i>Ld</i>-exosomes contribute to the host PAs pool and create an\nanti-inflammatory milieu. These findings highlight the essential role\nof PAs-enriched <i>Ld</i>-exosomes in parasite survival\nand establishing a pro-parasitic environment in the host macrophage.