# Inhibition of Wnt signaling in primary human hepatocytes promotes Plasmodium falciparum liver stage development

## TL;DR

Researchers found that inhibiting the Wnt signaling pathway in human liver cells improves the development of malaria parasites in lab cultures, helping study potential treatments.

## Contribution

A novel in vitro model for studying Plasmodium falciparum liver stages by inhibiting Wnt signaling in primary human hepatocytes.

## Key findings

- Inhibiting Wnt signaling in hepatocytes improves Plasmodium falciparum liver stage development.
- Host signaling pathways influence hepatocyte dedifferentiation and parasite permissiveness.
- Improved in vitro model retains hepatocyte metabolic activity while supporting parasite growth.

## Abstract

After infection of the human host, the first stage of the Plasmodium falciparum (Pf) lifecycle takes place in the liver. Understanding of host-parasite interactions during liver stage development is compromised by the rapid loss of functionality and Pf permissiveness of cultured primary human hepatocytes (PHHs). Here, we substantially delay the loss of Pf permissiveness by using a medium containing serum-replacement and signal transduction inhibitors. We analyzed and integrated transcriptomic profiles of cultured PHHs with the phenotypic presentation of developing Pf liver stages, revealing a number of host signaling pathways that contributed to dedifferentiation of hepatocytes and influenced Pf liver stage development. In particular, inhibition of the Wnt pathway showed a significant positive impact on size and maturity of Pf liver stage schizonts, while retaining the metabolic activity and epithelial nature of PHHs. Therefore, our study provides insights into hepatocyte characteristics that are important for Pf permissiveness and an improved in vitro liver stage model. This should facilitate identification and development of novel therapeutic strategies for Pf liver stages.

Despite substantial elimination and control measures, malaria still causes mortality and global disease burden. Liver stage development of the malaria parasite is a critical first step preceding clinical symptoms and is a potent target of antimalarial vaccine/drug development. However, we lack sufficient understanding of critical components of the host hepatocyte environment supporting or preventing liver stage parasite development. In this study, we observed substantial decline in the ability of cultured primary human hepatocytes to support parasite development and identified molecular signatures and altered activity of host signaling pathways associated with this loss of permissiveness. Specifically, we demonstrate the impact of the Wnt pathway on the growth and maturation of liver stage parasites in cultured primary human hepatocytes. We thus provide insight into how host hepatocyte homeostasis can impact liver stage parasite development and pave the way for further dissection of host-pathogen interactions and development of improved intervention strategies.