Abstract
SummaryAsymptomatic and obligatory liver stage (LS) infection of Plasmodium parasites presents an attractive target for antimalarial vaccine and drug development. Lack of robust cellular models to study LS infection has hindered the discovery and validation of host genes essential for intrahepatic parasite development. Here, we present a chemically differentiated mouse embryonic stem cell (ESC)-based LS model, which supports complete development of Plasmodium berghei exoerythrocytic forms (EEFs) and can be used to define new host-parasite interactions. Using our model, we established that host Pnpla2, coding for adipose triglyceride lipase, is dispensable for P. berghei EEF development. In addition, we also evaluated in-vitro-differentiated human hepatocyte-like cells (iHLCs) to study LS of P. berghei and found it to be a sub-optimal infection model. Overall, our results present a new mouse ESC-based P. berghei LS infection model that can be utilized to study the impact of host genetic variation on parasite development.
Highlights
Malaria is a devastating mosquito-borne infectious disease which caused an estimated 405,000 deaths worldwide in 2018, with 93% of the cases occurring in Africa (World Health Organization, 2019)
JM8.N4 mouse embryonic stem cell (ESC) show more uniform differentiation compared to E14 mouse ESCs, which still have a few colonies of undifferentiated cells left after MBA treatment
Our results demonstrate that treatment with MBA is a robust differentiation protocol which renders JM8.N4 and E14 mouse ESCs fully supportive of P. berghei liver stage (LS) development
Summary
Malaria is a devastating mosquito-borne infectious disease which caused an estimated 405,000 deaths worldwide in 2018, with 93% of the cases occurring in Africa (World Health Organization, 2019). A cycle of human malaria infection begins when an infected Anopheles mosquito inoculates Plasmodium sporozoites into the skin of a vertebrate host (Amino et al, 2006), from where the parasites trickle into the circulation and migrate toward liver to invade hepatocytes and form exoerythrocytic forms (EEFs) enclosed within the parasitophorous vacuole. Hepatoma cells exhibit low abundance of drug metabolizing enzymes and transporters (Guo et al, 2011), altered glycogen synthase kinase 3b (Desbois-mouthon et al, 2002), and Toll-like receptor 3 signaling (Khvalevsky et al, 2007), displaying phenotypes not observed in primary hepatocytes. Both, primary hepatocytes and hepatoma cell lines are acquired from a small group of donors representing limited genetic diversity within the population. Induced pluripotent stem cells (iPSCs), can be derived from diverse human subjects allowing generation of customized infection models and studying donor-specific infection phenotypes or responses
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