Development of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures

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

doi:10.1038/s41467-023-40298-7

Development of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	4631
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-40298-7
Publication status	Published - Dec 2023

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Yang, A. S. P., Dutta, D., Kretzschmar, K., Hendriks, D., Puschhof, J., Hu, H., Boonekamp, K. E., van Waardenburg, Y., Chuva de Sousa Lopes, S. M., van Gemert, G. J., de Wilt, J. H. W., Bousema, T., Clevers, H., & Sauerwein, R. W. (2023). Development of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures. Nature Communications, 14(1), Article 4631. https://doi.org/10.1038/s41467-023-40298-7

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title = "Development of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures",

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.",

author = "Yang, \{Annie S.P.\} and Devanjali Dutta and Kai Kretzschmar and Delilah Hendriks and Jens Puschhof and Huili Hu and Boonekamp, \{Kim E.\} and \{van Waardenburg\}, Youri and \{Chuva de Sousa Lopes\}, \{Susana M.\} and \{van Gemert\}, \{Geert Jan\} and \{de Wilt\}, \{Johannes H.W.\} and Teun Bousema and Hans Clevers and Sauerwein, \{Robert W.\}",

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year = "2023",

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doi = "10.1038/s41467-023-40298-7",

language = "English",

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journal = "Nature Communications",

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Yang, ASP, Dutta, D, Kretzschmar, K, Hendriks, D, Puschhof, J, Hu, H, Boonekamp, KE, van Waardenburg, Y, Chuva de Sousa Lopes, SM, van Gemert, GJ, de Wilt, JHW, Bousema, T, Clevers, H & Sauerwein, RW 2023, 'Development of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures', Nature Communications, vol. 14, no. 1, 4631. https://doi.org/10.1038/s41467-023-40298-7

TY - JOUR

T1 - Development of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures

AU - Yang, Annie S.P.

AU - Dutta, Devanjali

AU - Kretzschmar, Kai

AU - Hendriks, Delilah

AU - Puschhof, Jens

AU - Hu, Huili

AU - Boonekamp, Kim E.

AU - van Waardenburg, Youri

AU - Chuva de Sousa Lopes, Susana M.

AU - van Gemert, Geert Jan

AU - de Wilt, Johannes H.W.

AU - Bousema, Teun

AU - Clevers, Hans

AU - Sauerwein, Robert W.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85166427527

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DO - 10.1038/s41467-023-40298-7

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AN - SCOPUS:85166427527

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4631

ER -

Development of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures

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