Reference - Detail
| RRC ID | 87903 |
|---|---|
| Author | Ghosh S, Chigicherla KV, Dasgupta S, Goto Y, Mukherjee B. |
| Title | Oxidative stress-driven enhanced iron production and scavenging through Ferroportin reorientation worsens anemia in antimony-resistant Leishmania donovani infection. |
| Journal | PLoS Pathog |
| Abstract |
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. |
| Volume | 21(1) |
| Pages | e1012858 |
| Published | 2025-1-1 |
| DOI | 10.1371/journal.ppat.1012858 |
| PII | PPATHOGENS-D-24-00843 |
| PMID | 39888953 |
| PMC | PMC11785346 |
| MeSH | Animals Antimony* / pharmacology Antiprotozoal Agents / pharmacology Cation Transport Proteins* / metabolism Drug Resistance Ferroportin Humans Iron* / metabolism Leishmania donovani* / drug effects Leishmania donovani* / metabolism Leishmaniasis, Visceral* / drug therapy Leishmaniasis, Visceral* / metabolism Leishmaniasis, Visceral* / parasitology Macrophages / metabolism Macrophages / parasitology Mice Oxidative Stress* / drug effects Reactive Oxygen Species / metabolism |
| IF | 6.218 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 7 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Pathogenic eukaryotic microorganisms | Leishmania donovani D10, Ld003 |