Development of Plasmodium Falciparum Liver-stages in Hepatocytes Derived from Human Fetal Liver Organoid Cultures

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Aug 2

PMID 37532704

Authors

Annie S P Yang

Devanjali Dutta

Kai Kretzschmar

Delilah Hendriks

Jens Puschhof

Huili Hu

Kim E Boonekamp

Youri van Waardenburg

Susana M Chuva de Sousa Lopes

Geert-Jan van Gemert

Johannes H W de Wilt

Teun Bousema

Hans Clevers

Robert W Sauerwein

Affiliations

Soon will be listed here.

Abstract

Plasmodium falciparum (Pf) parasite development in liver represents the initial step of the life-cycle in the human host after a Pf-infected mosquito bite. While an attractive stage for life-cycle interruption, understanding of parasite-hepatocyte interaction is inadequate due to limitations of existing in vitro models. We explore the suitability of hepatocyte organoids (HepOrgs) for Pf-development and show that these cells permitted parasite invasion, differentiation and maturation of different Pf strains. Single-cell messenger RNA sequencing (scRNAseq) of Pf-infected HepOrg cells has identified 80 Pf-transcripts upregulated on day 5 post-infection. Transcriptional profile changes are found involving distinct metabolic pathways in hepatocytes with Scavenger Receptor B1 (SR-B1) transcripts highly upregulated. A novel functional involvement in schizont maturation is confirmed in fresh primary hepatocytes. Thus, HepOrgs provide a strong foundation for a versatile in vitro model for Pf liver-stages accommodating basic biological studies and accelerated clinical development of novel tools for malaria control.

Citing Articles

Liver stage P. falciparum antigens highly targeted by CD4+ T cells in malaria-exposed Ugandan children.

Acevedo G, Samiee S, Ilala M, Levan J, Olive M, Hunter R PLoS Pathog. 2025; 21(2):e1012943.

PMID: 39993000 PMC: 11906071. DOI: 10.1371/journal.ppat.1012943.

Spatially defined microenvironment for engineering organoids.

Zhang Y, Qi F, Chen P, Liu B, Li Y Biophys Rev (Melville). 2024; 5(4):041302.

PMID: 39679203 PMC: 11646138. DOI: 10.1063/5.0198848.

Human liver organoids are susceptible to Plasmodium vivax infection.

Nitaramorn N, Kobpornchai P, Tongkrajang N, Chaisri U, Imwong M, Kulkeaw K Malar J. 2024; 23(1):368.

PMID: 39639330 PMC: 11622667. DOI: 10.1186/s12936-024-05202-8.

Emerging biotechnologies for engineering liver organoids.

Zhao J, Zhi Y, Ren H, Wang J, Zhao Y Bioact Mater. 2024; 45:1-18.

PMID: 39588483 PMC: 11585797. DOI: 10.1016/j.bioactmat.2024.11.002.

A 3D organoid platform that supports liver-stage infection can be used to identify intrahepatic antimalarial drugs.

Rao S, Romal S, Torenvliet B, Slotman J, Huijs T, Mahmoudi T Heliyon. 2024; 10(10):e30740.

PMID: 38770342 PMC: 11103482. DOI: 10.1016/j.heliyon.2024.e30740.

References

Foquet L, Hermsen C, Verhoye L, van Gemert G, Cortese R, Nicosia A . Anti-CD81 but not anti-SR-BI blocks Plasmodium falciparum liver infection in a humanized mouse model. J Antimicrob Chemother. 2015; 70(6):1784-7. DOI: 10.1093/jac/dkv019. View

Albuquerque S, Carret C, Grosso A, Tarun A, Peng X, Kappe S . Host cell transcriptional profiling during malaria liver stage infection reveals a coordinated and sequential set of biological events. BMC Genomics. 2009; 10:270. PMC: 2706893. DOI: 10.1186/1471-2164-10-270. View

Rodrigues C, Hannus M, Prudencio M, Martin C, Goncalves L, Portugal S . Host scavenger receptor SR-BI plays a dual role in the establishment of malaria parasite liver infection. Cell Host Microbe. 2008; 4(3):271-82. DOI: 10.1016/j.chom.2008.07.012. View

Ponnudurai T, Lensen A, van Gemert G, Bensink M, Bolmer M, Meuwissen J . Infectivity of cultured Plasmodium falciparum gametocytes to mosquitoes. Parasitology. 1989; 98 Pt 2:165-73. DOI: 10.1017/s0031182000062065. View

Labaied M, Jayabalasingham B, Bano N, Cha S, Sandoval J, Guan G . Plasmodium salvages cholesterol internalized by LDL and synthesized de novo in the liver. Cell Microbiol. 2010; 13(4):569-86. DOI: 10.1111/j.1462-5822.2010.01555.x. View

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

Barata L, Houze P, Boutbibe K, Zanghi G, Franetich J, Mazier D . In Vitro Analysis of the Interaction between Atovaquone and Proguanil against Liver Stage Malaria Parasites. Antimicrob Agents Chemother. 2016; 60(7):4333-5. PMC: 4914690. DOI: 10.1128/AAC.01685-15. View

Roth A, Maher S, Conway A, Ubalee R, Chaumeau V, Andolina C . A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum. Nat Commun. 2018; 9(1):1837. PMC: 5943321. DOI: 10.1038/s41467-018-04221-9. View

Kaushansky A, Douglass A, Arang N, Vigdorovich V, Dambrauskas N, Kain H . Malaria parasites target the hepatocyte receptor EphA2 for successful host infection. Science. 2015; 350(6264):1089-92. PMC: 4783171. DOI: 10.1126/science.aad3318. View

10.

Muraro M, Dharmadhikari G, Grun D, Groen N, Dielen T, Jansen E . A Single-Cell Transcriptome Atlas of the Human Pancreas. Cell Syst. 2016; 3(4):385-394.e3. PMC: 5092539. DOI: 10.1016/j.cels.2016.09.002. View

11.

Tarun A, Peng X, Dumpit R, Ogata Y, Silva-Rivera H, Camargo N . A combined transcriptome and proteome survey of malaria parasite liver stages. Proc Natl Acad Sci U S A. 2008; 105(1):305-10. PMC: 2224207. DOI: 10.1073/pnas.0710780104. View

12.

Xiang C, Du Y, Meng G, Yi L, Sun S, Song N . Long-term functional maintenance of primary human hepatocytes in vitro. Science. 2019; 364(6438):399-402. DOI: 10.1126/science.aau7307. View

13.

Hashimshony T, Senderovich N, Avital G, Klochendler A, de Leeuw Y, Anavy L . CEL-Seq2: sensitive highly-multiplexed single-cell RNA-Seq. Genome Biol. 2016; 17:77. PMC: 4848782. DOI: 10.1186/s13059-016-0938-8. View

14.

Tripathi A, Mlambo G, Kanatani S, Sinnis P, Dimopoulos G . Plasmodium falciparum Gametocyte Culture and Mosquito Infection Through Artificial Membrane Feeding. J Vis Exp. 2020; (161). PMC: 8216103. DOI: 10.3791/61426. View

15.

Boj S, van Es J, Huch M, Li V, Jose A, Hatzis P . Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand. Cell. 2012; 151(7):1595-607. DOI: 10.1016/j.cell.2012.10.053. View

16.

Ifediba T, Vanderberg J . Complete in vitro maturation of Plasmodium falciparum gametocytes. Nature. 1981; 294(5839):364-6. DOI: 10.1038/294364a0. View

17.

Silvie O, Greco C, Franetich J, Dubart-Kupperschmitt A, Hannoun L, van Gemert G . Expression of human CD81 differently affects host cell susceptibility to malaria sporozoites depending on the Plasmodium species. Cell Microbiol. 2006; 8(7):1134-46. DOI: 10.1111/j.1462-5822.2006.00697.x. View

18.

Clevers H . Modeling Development and Disease with Organoids. Cell. 2016; 165(7):1586-1597. DOI: 10.1016/j.cell.2016.05.082. View

19.

Yang A, van Waardenburg Y, van de Vegte-Bolmer M, van Gemert G, Graumans W, de Wilt J . Zonal human hepatocytes are differentially permissive to Plasmodium falciparum malaria parasites. EMBO J. 2021; 40(6):e106583. PMC: 7957391. DOI: 10.15252/embj.2020106583. View

20.

Naujok O, Lentes J, Diekmann U, Davenport C, Lenzen S . Cytotoxicity and activation of the Wnt/beta-catenin pathway in mouse embryonic stem cells treated with four GSK3 inhibitors. BMC Res Notes. 2014; 7:273. PMC: 4008422. DOI: 10.1186/1756-0500-7-273. View