Plasmodium Vivax Liver Stage Development and Hypnozoite Persistence in Human Liver-chimeric Mice

Overview

Journal Cell Host Microbe

Publisher Cell Press

Specialties Infectious Diseases
Microbiology

Date 2015 Mar 25

PMID 25800544

Citations 117

Authors

Sebastian A Mikolajczak

Ashley M Vaughan

Niwat Kangwanrangsan

Wanlapa Roobsoong

Matthew Fishbaugher

Narathatai Yimamnuaychok

Nastaran Rezakhani

Viswanathan Lakshmanan

Naresh Singh

Alexis Kaushansky

Nelly Camargo

Michael Baldwin

Scott E Lindner

John H Adams

Jetsumon Sattabongkot

Jetsumon Prachumsri

Stefan H I Kappe

Affiliations

Soon will be listed here.

Abstract

Plasmodium vivax malaria is characterized by periodic relapses of symptomatic blood stage parasite infections likely initiated by activation of dormant liver stage parasites-hypnozoites. The lack of tractable P. vivax animal models constitutes an obstacle in examining P. vivax liver stage infection and drug efficacy. To overcome this obstacle, we have used human liver-chimeric (huHep) FRG KO mice as a model for P. vivax infection. FRG KO huHep mice support P. vivax sporozoite infection, liver stage development, and hypnozoite formation. We show complete P. vivax liver stage development, including maturation into infectious exo-erythrocytic merozoites as well as the formation and persistence of hypnozoites. Prophylaxis or treatment with the antimalarial primaquine can prevent and eliminate liver stage infection, respectively. Thus, P. vivax-infected FRG KO huHep mice are a model to investigate liver stage development and dormancy and may facilitate the discovery of drugs targeting relapsing malaria.

Citing Articles

Genome-wide gene expression profiles throughout human malaria parasite liver stage development in humanized mice.

Zanghi G, Patel H, Smith J, Camargo N, Bae Y, Hesping E Nat Microbiol. 2025; 10(2):569-584.

PMID: 39891010 PMC: 11790487. DOI: 10.1038/s41564-024-01905-5.

Potent AMA1-specific human monoclonal antibody against Plasmodium vivax Pre-erythrocytic and Blood Stages.

Winnicki A, Dietrich M, Yeoh L, Carias L, Roobsoong W, Drago C Nat Commun. 2024; 15(1):10556.

PMID: 39632799 PMC: 11618605. DOI: 10.1038/s41467-024-53848-4.

Integral Solvent-Induced Protein Precipitation for Target-Engagement Studies in .

Bravo P, Bizzarri L, Steinbrunn D, Lohse J, Hirsch A, Maser P ACS Infect Dis. 2024; 10(12):4073-4086.

PMID: 39631773 PMC: 11650652. DOI: 10.1021/acsinfecdis.4c00418.

Mice Engrafted with Human Liver Cells.

de Jong Y Semin Liver Dis. 2024; 44(4):405-415.

PMID: 39265638 PMC: 11620938. DOI: 10.1055/s-0044-1790601.

Detection of Duffy blood group genotypes and submicroscopic Plasmodium infections using molecular diagnostic assays in febrile malaria patients.

Abagero B, Rama R, Obeid A, Tolosa T, Lukas B, Teka T Malar J. 2024; 23(1):194.

PMID: 38902674 PMC: 11191254. DOI: 10.1186/s12936-024-04875-5.

References

Mueller A, Camargo N, Kaiser K, Andorfer C, Frevert U, Matuschewski K . Plasmodium liver stage developmental arrest by depletion of a protein at the parasite-host interface. Proc Natl Acad Sci U S A. 2005; 102(8):3022-7. PMC: 548321. DOI: 10.1073/pnas.0408442102. View

Elmendorf H, Haldar K . Identification and localization of ERD2 in the malaria parasite Plasmodium falciparum: separation from sites of sphingomyelin synthesis and implications for organization of the Golgi. EMBO J. 1993; 12(12):4763-73. PMC: 413923. DOI: 10.1002/j.1460-2075.1993.tb06165.x. View

Krotoski W, BRAY R, Garnham P, Gwadz R, Killick-Kendrick R, Draper C . Observations on early and late post-sporozoite tissue stages in primate malaria. II. The hypnozoite of Plasmodium cynomolgi bastianellii from 3 to 105 days after infection, and detection of 36- to 40-hour pre-erythrocytic forms. Am J Trop Med Hyg. 1982; 31(2):211-25. View

Carlton J, Sina B, Adams J . Why is Plasmodium vivax a neglected tropical disease?. PLoS Negl Trop Dis. 2011; 5(6):e1160. PMC: 3125139. DOI: 10.1371/journal.pntd.0001160. View

MacKellar D, ONeill M, Aly A, Sacci Jr J, Cowman A, Kappe S . Plasmodium falciparum PF10_0164 (ETRAMP10.3) is an essential parasitophorous vacuole and exported protein in blood stages. Eukaryot Cell. 2010; 9(5):784-94. PMC: 2863949. DOI: 10.1128/EC.00336-09. View

Rosenberg R, Wirtz R, Lanar D, Sattabongkot J, Hall T, Waters A . Circumsporozoite protein heterogeneity in the human malaria parasite Plasmodium vivax. Science. 1989; 245(4921):973-6. DOI: 10.1126/science.2672336. View

Krotoski W, Garnham P, BRAY R, Krotoski D, Killick-Kendrick R, Draper C . Observations on early and late post-sporozoite tissue stages in primate malaria. I. Discovery of a new latent form of Plasmodium cynomolgi (the hypnozoite), and failure to detect hepatic forms within the first 24 hours after infection. Am J Trop Med Hyg. 1982; 31(1):24-35. View

Anstey N, Douglas N, Poespoprodjo J, Price R . Plasmodium vivax: clinical spectrum, risk factors and pathogenesis. Adv Parasitol. 2012; 80:151-201. DOI: 10.1016/B978-0-12-397900-1.00003-7. View

Kaiser K, Matuschewski K, Camargo N, Ross J, Kappe S . Differential transcriptome profiling identifies Plasmodium genes encoding pre-erythrocytic stage-specific proteins. Mol Microbiol. 2004; 51(5):1221-32. DOI: 10.1046/j.1365-2958.2003.03909.x. View

10.

Bissig K, Le T, Woods N, Verma I . Repopulation of adult and neonatal mice with human hepatocytes: a chimeric animal model. Proc Natl Acad Sci U S A. 2007; 104(51):20507-11. PMC: 2154461. DOI: 10.1073/pnas.0710528105. View

11.

Galinski M, Meyer E, Barnwell J . Plasmodium vivax: modern strategies to study a persistent parasite's life cycle. Adv Parasitol. 2013; 81:1-26. DOI: 10.1016/B978-0-12-407826-0.00001-1. View

12.

Miller J, Harupa A, Kappe S, Mikolajczak S . Plasmodium yoelii macrophage migration inhibitory factor is necessary for efficient liver-stage development. Infect Immun. 2012; 80(4):1399-407. PMC: 3318411. DOI: 10.1128/IAI.05861-11. View

13.

Vaughan A, ONeill M, Tarun A, Camargo N, Phuong T, Aly A . Type II fatty acid synthesis is essential only for malaria parasite late liver stage development. Cell Microbiol. 2008; 11(3):506-20. PMC: 2688669. DOI: 10.1111/j.1462-5822.2008.01270.x. View

14.

Markus M . Malaria: origin of the term "hypnozoite". J Hist Biol. 2010; 44(4):781-6. DOI: 10.1007/s10739-010-9239-3. View

15.

Silvie O, Briquet S, Muller K, Manzoni G, Matuschewski K . Post-transcriptional silencing of UIS4 in Plasmodium berghei sporozoites is important for host switch. Mol Microbiol. 2014; 91(6):1200-13. DOI: 10.1111/mmi.12528. View

16.

Sattabongkot J, Yimamnuaychoke N, Leelaudomlipi S, Rasameesoraj M, Jenwithisuk R, Coleman R . Establishment of a human hepatocyte line that supports in vitro development of the exo-erythrocytic stages of the malaria parasites Plasmodium falciparum and P. vivax. Am J Trop Med Hyg. 2006; 74(5):708-15. View

17.

Hollingdale M, Collins W, CAMPBELL C, Schwartz A . In vitro culture of two populations (dividing and nondividing) of exoerythrocytic parasites of Plasmodium vivax. Am J Trop Med Hyg. 1985; 34(2):216-22. DOI: 10.4269/ajtmh.1985.34.216. View

18.

Guerra C, Howes R, Patil A, Gething P, Van Boeckel T, Temperley W . The international limits and population at risk of Plasmodium vivax transmission in 2009. PLoS Negl Trop Dis. 2010; 4(8):e774. PMC: 2914753. DOI: 10.1371/journal.pntd.0000774. View

19.

Baird J . Malaria caused by Plasmodium vivax: recurrent, difficult to treat, disabling, and threatening to life--the infectious bite preempts these hazards. Pathog Glob Health. 2014; 107(8):475-9. PMC: 4073528. DOI: 10.1179/2047772413Z.000000000179. View

20.

March S, Ng S, Velmurugan S, Galstian A, Shan J, Logan D . A microscale human liver platform that supports the hepatic stages of Plasmodium falciparum and vivax. Cell Host Microbe. 2013; 14(1):104-15. PMC: 3780791. DOI: 10.1016/j.chom.2013.06.005. View