Plasmodium vivax latent liver infection is characterized by persistent hypnozoites, hypnozoite-derived schizonts, and time-dependent efficacy of primaquine

Flannery, Erika L.; Kangwanrangsan, Niwat; Chuenchob, Vorada; Roobsoong, Wanlapa; Fishbaugher, Matthew; Zhou, Kevin; Billman, Zachary P.; Martinson, Thomas; Olsen, Tayla M.; Schäfer, Carola; Campo, Brice; Murphy, Sean C.; Mikolajczak, Sebastian A.; Kappe, Stefan H. I.; Sattabongkot, Jetsumon

doi:10.1016/j.omtm.2022.07.016

Cited by 18 publications

(16 citation statements)

References 63 publications

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“…The role of this model in the radical cure drug development cascade may need to be reevaluated as some compounds identified as promising for the radical cure of P. vivax may be abandoned too quickly due to the lack of activity against P. cynomolgi. This result highlights the need for further development and validation of P. vivax -specific animal models 65 . As a whole this report adds to the broader discussion surrounding the successes and challenges of drug repurposing 66 .…”

Section: Discussionmentioning

confidence: 91%

“…However, this result might also be attributed to differential metabolism in human and monkey hepatocytes ( 26 ). Regardless, these results highlight that in vivo P. vivax relapse models should be further developed and validated, as those hits lacking activity in P. cynomolgi might be abandoned for no other reason than the inability to demonstrate in vivo efficacy prior to first-in-human studies ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

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A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways inPlasmodium vivaxHypnozoites

Maher

Bakowski

Vantaux

et al. 2023

Preprint

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Radical cure of Plasmodium vivax malaria must include elimination of quiescent "hypnozoite" forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets, we screened the Repurposing, Focused Rescue, and Accelerated Medchem library against P. vivax liver stages and identified the DNA methyltransferase inhibitors hydralazine and cadralazine as active against hypnozoites. We then used bisulfite sequencing and immunostaining to identify cytosine modifications in the infectious stage (sporozoites) and liver stages, respectively. A subsequent screen of epigenetic inhibitors revealed hypnozoites are broadly sensitive to histone acetyltransferase and methyltransferase inhibitors, indicating that several epigenetic mechanisms are likely modulating hypnozoite persistence. Our data present an avenue for the discovery and development of improved radical cure antimalarials.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways inPlasmodium vivaxHypnozoites

Maher

Bakowski

Vantaux

et al. 2023

Preprint

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“…The elimination of gametocytes in vitro [ 58 ] or in vivo by PQ and the prophylactic usage thereof aside, the drug is, otherwise, usually only thought of as a hypnozoitocidal agent and one which also inactivates schizonts in the liver [ 59 ]. This hitherto presumed contribution to the radical cure of P. vivax malaria has now actually been demonstrated microscopically in vivo, albeit in humanized mice [ 60 ]. These findings follow the confirmation by Voorberg-van der Wel et al that hypnozoites in liver cells do in fact activate [ 61 , 62 ], as had been assumed for decades ( Table 1 ).…”

Section: Inactivation Of Intra-erythrocytic Stages Of Plasm...mentioning

confidence: 99%

Putative Contribution of 8-Aminoquinolines to Preventing Recrudescence of Malaria

Markus

2023

TropicalMed

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Enhanced therapeutic efficacy achieved in treating Plasmodium vivax malaria with an 8-aminoquinoline (8-AQ) drug such as primaquine (PQ) together with a partner drug such as chloroquine (CQ) is usually explained as CQ inhibiting asexual parasites in the bloodstream and PQ acting against liver stages. However, PQ’s contribution, if any, to inactivating non-circulating, extra-hepatic asexual forms, which make up the bulk of the parasite biomass in chronic P. vivax infections, remains unclear. In this opinion article, I suggest that, considering its newly described mode of action, PQ might be doing something of which we are currently unaware.

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“…[21] P. vivax and P. ovale, the causative agents of malaria tertiana, are able to form dormant developmental stages (hypnozoites). [22] These can persist within the liver and can initiate a relapse of malaria even years after the actual infection. The liver schizogony concludes when the newly produced merozoites are packed into host cell membranederived vesicles (merosomes) and transported past the liver's residential macrophages (Kupffer cells) into the liver sinusoids where they immediately infect red blood cells (RBC) to commence the erythrocytic schizogony [23,24] (Figure 1).…”

Section: F I G U R Ementioning

confidence: 99%

“…[27,28] The number of produced merozoites varies between the Plasmodium species. P. falciparum produces up to 32 merozoites, while P. vivax (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), P. ovale (6)(7)(8)(9)(10)(11)(12)(13)(14), P. malariae (6)(7)(8)(9)(10)(11)(12), and P.…”

Section: F I G U R Ementioning

confidence: 99%

Novel secretory organelles of parasite origin ‐ at the center of host‐parasite interaction

Bekić,

Kilian

2023

BioEssays

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Reorganization of cell organelle‐deprived host red blood cells by the apicomplexan malaria parasite Plasmodium falciparum enables their cytoadherence to endothelial cells that line the microvasculature. This increases the time red blood cells infected with mature developmental stages remain within selected organs such as the brain to avoid the spleen passage, which can lead to severe complications and cumulate in patient death. The Maurer's clefts are a novel secretory organelle of parasite origin established by the parasite in the cytoplasm of the host red blood cell in order to facilitate the establishment of cytoadherence by conducting the trafficking of immunovariant adhesins to the host cell surface. Another important function of the organelle is the sorting of other proteins the parasite traffics into its host cell. Although the organelle is of high importance for the pathology of malaria, additional putative functions, structure, and genesis remain shrouded in mystery more than a century after its discovery. In this review, we highlight our current knowledge about the Maurer's clefts and other novel secretory organelles established within the host cell cytoplasm by human‐pathogenic malaria parasites and other parasites that reside within human red blood cells.

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Plasmodium vivax latent liver infection is characterized by persistent hypnozoites, hypnozoite-derived schizonts, and time-dependent efficacy of primaquine

Cited by 18 publications

References 63 publications

A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways inPlasmodium vivaxHypnozoites

A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways inPlasmodium vivaxHypnozoites

Putative Contribution of 8-Aminoquinolines to Preventing Recrudescence of Malaria

Novel secretory organelles of parasite origin ‐ at the center of host‐parasite interaction

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