Addressing anemia severity in antimony-resistant Leishmania donovani infection at the nexus of oxidative outburst and iron transit

Despite the withdrawal of pentavalent-antimonials in treating Visceral leishmaniasis for more than a decade, recent clinical isolates of Leishmania donovani (LD) exhibit unresponsiveness towards pentavalent-antimony (LD-R). This antimony-unresponsiveness points towards a genetic adaptation that underpins LD-R’s evolutionary persistence and superiority over sensitive counterparts. This study highlights LD’s response to antimony exposure in terms of increased potential of scavenging host-derived iron within its parasitophorous vacuoles (PV). LD-R employs a strategy to both produce and rapidly scavenge host-iron in a ROS-dependant manner, and selectively reshuffle iron exporter, Ferroportin, around its PV. Higher iron utilization leads to subsequent iron-insufficiency, compensated by increased erythrophagocytosis facilitated by the breakdown of SIRPα, orchestrated by a complex interplay of two proteases, Furin and ADAM10. Understanding these mechanisms is crucial for managing LD-R infections and their associated complications, like anemia, and may also provide valuable insights into understanding resistance developed in other pathogens that rely on host iron.