Polyamine-Enriched Exosomes from <i>Leishmania donovani</i> Drive Host Macrophage Polarization via Immunometabolism Reprogramming

<i>Leishmania donovani</i> (<i>Ld</i>) promastigotes secrete exosomes that are crucial in host-pathogen interactions and intercellular communication by carrying parasite-specific molecules. Although the composition of cargos in <i>Leishmania</i> exosomes is known, the effects of the unique metabolic repertoire on immunometabolism rewiring of macrophage polarization are poorly understood. Interestingly, we found the enrichment of polyamines (PAs) such as spermidine and putrescine in the <i>Ld</i>-exosomes. Herein, we investigate the critical polycationic molecules and their crucial role in parasite survival. Our study shows that PA inhibition or depletion significantly impairs parasite growth and fitness, particularly in drug-resistant strains. Furthermore, we aimed to elucidate the impact of PAs-enriched <i>Ld</i>-exosomes on host macrophages. The data demonstrated that macrophages efficiently internalized these exosomes, leading to heightened phagocytic activity and infectivity. In addition, internalized <i>Ld</i>-exosomes induced M2 macrophage polarization characterized by elevated Arginase-1 expression and activity. The increased expression of the solute carrier gene (SLC3A2) and elevated intracellular spermidine levels suggest that <i>Ld</i>-exosomes contribute to the host PAs pool and create an anti-inflammatory milieu. These findings highlight the essential role of PAs-enriched <i>Ld</i>-exosomes in parasite survival and establishing a pro-parasitic environment in the host macrophage.