Human iPSC-Derived Hepatocyte-like Cells Support Plasmodium Liver-Stage Infection In Vitro

Abstract

SummaryMalaria eradication is a major goal in public health but is challenged by relapsing malaria species, expanding drug resistance, and the influence of host genetics on antimalarial drug efficacy. To overcome these hurdles, it is imperative to establish in vitro assays of liver-stage malaria for drug testing. Induced pluripotent stem cells (iPSC) potentially allow the assessment of donor-specific drug responses, and iPSC-derived hepatocyte-like cells (iHLCs) can facilitate the study of host genetics on host-pathogen interactions and the discovery of novel targets for antimalarial drug development. We establish in vitro liver-stage malaria infections in iHLCs using P. berghei, P. yoelii, P. falciparum, and P. vivax and show that differentiating cells acquire permissiveness to malaria infection at the hepatoblast stage. We also characterize antimalarial drug metabolism capabilities of iHLCs using prototypical antimalarial drugs and demonstrate that chemical maturation of iHLCs can improve their potential for antimalarial drug testing applications.

Current therapies and future possibilities for drug development against liver-stage malaria

“…Most importantly, unlike primary hepatocytes, the micropatterned hepatocytes can be maintained for several weeks, allowing for the study of hypnozoite biology. The Bhatia group further developed this microscale culture technology by demonstrating that this tissue engineering of the human liver can also be derived from induced pluripotent stem cells (iPSCs) (89). A similar coculturing strategy of cynomolgus monkey primary hepatocytes with another hepatoma cell line was used to support the development of hypnozoites from P. cynomolgi (90).…”

Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art

“…Accordingly, these questions should be addressed by the malaria community using the various malaria animal models and controlled human clinical trials. Recent advances in in vitro drug metabolism and malaria infection models will hopefully allow for more complete and expedited investigations of such questions (Furuya, Sa, Chitnis, Wellems, & Stedman, 2014;Ng, et al, 2015;Yang, Atkinson, & Di, 2015).…”

Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

“…iPSC-based drug screening has also been applied to diseases other than genetic disorders, such as infectious diseases [167]. iPSC-derived hepatocytes have been used to screen drugs for treating chronic infectious disease, such as hepatitis B and liver-stage malaria [172, 173]. High-throughput drug screenings have also been carried out to identify potential antiviral drugs using iPSC-derived cardiomyocytes and neurons from patient with viral cardiomyopathy or Zika virus infection [174, 175].…”