| 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
|
| Resource |
| Pathogenic eukaryotic microorganisms |
Leishmania donovani D10, Ld003 |
