Oxidative stress-driven enhanced iron production and scavenging through Ferroportin reorientation worsens anemia in antimony-resistant Leishmania donovani infection.
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&#...
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Public Library of Science (PLoS)
2025-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1012858 |
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| author | Souradeepa Ghosh Krishna Vamshi Chigicherla Shirin Dasgupta Yasuyuki Goto Budhaditya Mukherjee |
| author_facet | Souradeepa Ghosh Krishna Vamshi Chigicherla Shirin Dasgupta Yasuyuki Goto Budhaditya Mukherjee |
| author_sort | Souradeepa Ghosh |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0c7f335f65d24c0e9cec85571a36a675 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Pathogens |
| spelling | doaj-art-0c7f335f65d24c0e9cec85571a36a6752025-02-07T05:30:30ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-01-01211e101285810.1371/journal.ppat.1012858Oxidative stress-driven enhanced iron production and scavenging through Ferroportin reorientation worsens anemia in antimony-resistant Leishmania donovani infection.Souradeepa GhoshKrishna Vamshi ChigicherlaShirin DasguptaYasuyuki GotoBudhaditya MukherjeeDespite 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.https://doi.org/10.1371/journal.ppat.1012858 |
| spellingShingle | Souradeepa Ghosh Krishna Vamshi Chigicherla Shirin Dasgupta Yasuyuki Goto Budhaditya Mukherjee Oxidative stress-driven enhanced iron production and scavenging through Ferroportin reorientation worsens anemia in antimony-resistant Leishmania donovani infection. PLoS Pathogens |
| title | Oxidative stress-driven enhanced iron production and scavenging through Ferroportin reorientation worsens anemia in antimony-resistant Leishmania donovani infection. |
| title_full | Oxidative stress-driven enhanced iron production and scavenging through Ferroportin reorientation worsens anemia in antimony-resistant Leishmania donovani infection. |
| title_fullStr | Oxidative stress-driven enhanced iron production and scavenging through Ferroportin reorientation worsens anemia in antimony-resistant Leishmania donovani infection. |
| title_full_unstemmed | Oxidative stress-driven enhanced iron production and scavenging through Ferroportin reorientation worsens anemia in antimony-resistant Leishmania donovani infection. |
| title_short | Oxidative stress-driven enhanced iron production and scavenging through Ferroportin reorientation worsens anemia in antimony-resistant Leishmania donovani infection. |
| title_sort | oxidative stress driven enhanced iron production and scavenging through ferroportin reorientation worsens anemia in antimony resistant leishmania donovani infection |
| url | https://doi.org/10.1371/journal.ppat.1012858 |
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