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
N1 - © 2023. The Author(s).
PY - 2023/8/2
Y1 - 2023/8/2
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.
KW - Humans
KW - Plasmodium falciparum/genetics
KW - Liver/metabolism
KW - Hepatocytes/metabolism
KW - Malaria/parasitology
KW - Organoids/metabolism
KW - Malaria, Falciparum/parasitology
U2 - 10.1038/s41467-023-40298-7
DO - 10.1038/s41467-023-40298-7
M3 - Article
C2 - 37532704
SN - 2041-1723
VL - 14
SP - 4631
JO - Nature Communications
JF - Nature Communications
IS - 1
ER -