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

• Published in: Molecular therapy. Methods & clinical development Vol. 26; pp. 427 - 440
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.09.2022; American Society of Gene & Cell Therapy; Elsevier
• Subjects: dormancy; hypnozoite; latency; liver-chimeric humanized mice; malaria; Original; Plasmodium vivax; primaquine; relapse; Plasmodium vivax; hypnozoite; primaquine; relapse; dormancy; latency; liver-chimeric humanized mice; malaria
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2022.07.016

Plasmodium vivax is a malaria-causing pathogen that establishes a dormant form in the liver (the hypnozoite), which can activate weeks, months, or years after the primary infection to cause a relapse, characterized by secondary blood-stage infection. These asymptomatic and undetectable latent liver infections present a significant obstacle to the goal of global malaria eradication. We use a human liver-chimeric mouse model (FRG huHep) to study P. vivax hypnozoite latency and activation in an in vivo model system. Functional activation of hypnozoites and formation of secondary schizonts is demonstrated by first eliminating primary liver schizonts using a schizont-specific antimalarial tool compound, and then measuring recurrence of secondary liver schizonts in the tissue and an increase in parasite RNA within the liver. We also reveal that, while primaquine does not immediately eliminate hypnozoites from the liver, it arrests developing schizonts and prevents activation of hypnozoites, consistent with its clinical activity in humans. Our findings demonstrate that the FRG huHep model can be used to study the biology of P. vivax infection and latency and assess the activity of anti-relapse drugs. [Display omitted] The liver-chimeric humanized mouse model is used to show the effect of P. vivax standard of care drugs on hypnozoites in vivo. Immediate clearance of parasites is not observed, yet increased incubation time together with removal of arrested drug-treated parasites with tool compounds allows the testing of radical cure drugs.