Oxidative stress-driven enhanced iron production and scavenging through Ferroportin reorientation worsens anemia in antimony-resistant Leishmania donovani infection.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101238921 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7374 (Electronic) Linking ISSN: 15537366 NLM ISO Abbreviation: PLoS Pathog Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Leishmania donovani*/drug effects ; Leishmania donovani*/metabolism ; Oxidative Stress*/drug effects ; Leishmaniasis, Visceral*/metabolism ; Leishmaniasis, Visceral*/drug therapy ; Leishmaniasis, Visceral*/parasitology ; Iron*/metabolism ; Antimony*/pharmacology ; Cation Transport Proteins*/metabolism; Animals ; Ferroportin ; Mice ; Macrophages/metabolism ; Macrophages/parasitology ; Reactive Oxygen Species/metabolism ; Drug Resistance ; Humans ; Antiprotozoal Agents/pharmacology

Competing Interests: The authors have declared that no competing interests exist.
Despite the withdrawal of pentavalent-antimonials in treating Visceral leishmaniasis from India, 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 dominance over sensitive counterparts (LD-S). This study highlights how LD evolutionarily tackled antimony exposure and gained increased potential of scavenging host-iron within its parasitophorous vacuoles (PV) to support its aggressive proliferation. Even though anti-leishmanial activity of pentavalent antimonials relies on triggering oxidative outburst, LD-R exhibits a surprising strategy of promoting reactive oxygen species (ROS) generation in infected macrophages. An inherent metabolic shift from glycolysis to Pentose Phosphate shunt allows LD-R to withstand elevated ROS by sustaining heightened levels of NADPH. Elevated ROS levels on the other hand trigger excess iron production, and LD-R capitalizes on this surplus iron by selectively reshuffling macrophage-surface iron exporter, Ferroportin, around its PV thereby gaining a survival edge as a heme-auxotroph. Higher iron utilization by LD-R leads to subsequent iron insufficiency, compensated by increased erythrophagocytosis through the breakdown of SIRPα-CD47 surveillance, 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 severe anemia, and may also provide valuable mechanistic insights into understanding drug unresponsiveness developed in other intracellular pathogens that rely on host iron.
(Copyright: © 2025 Ghosh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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E1UOL152H7 (Iron)
9IT35J3UV3 (Antimony)
0 (Ferroportin)
0 (Cation Transport Proteins)
0 (Reactive Oxygen Species)
0 (Antiprotozoal Agents)

Date Created: 20250131 Date Completed: 20250504 Latest Revision: 20250504

20250505

PMC11785346

10.1371/journal.ppat.1012858

39888953