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Biomaterials. 2019 Sep;216:119221. doi: 10.1016/j.biomaterials.2019.05.032. Epub 2019 May 22.

Hepatic spheroids used as an in vitro model to study malaria relapse.

Author information

1
Novartis Institute for Tropical Diseases, 138670, Singapore; Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand; Singapore Immunology Network (SIgN), A*STAR, 138648, Singapore.
2
Invitrocue Pte Ltd. 138667, Singapore.
3
Novartis Institute for Tropical Diseases, 138670, Singapore; Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand.
4
Novartis Institute for Tropical Diseases, 138670, Singapore.
5
Novartis Institute for Tropical Diseases, 138670, Singapore; Université des Sciences, des Techniques et des Technologies de Bamako (USTTB); MRTC - DEAP - Faculty of Pharmacy, Bamako, Mali.
6
Invitrocue Pte Ltd. 138667, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University Health System, 117597, Singapore.
7
Department of Entomology, Armed Forces Research Institute of Medical Science (AFRIMS), Bangkok 10400,Thailand.
8
Department of Veterinary Medicine, Armed Forces Research Institute of Medical Science (AFRIMS), Bangkok 10400,Thailand.
9
Mechanobiology Institute, National University of Singapore, 117411, Singapore.
10
Shoklo Malaria Research Unit (SMRU), Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
11
Institute of Bioengineering and Nanotechnology, A*STAR, 138669, Singapore.
12
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 119077, Singapore.
13
Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand.
14
Laboratory Animal Services, Scientific Operations, Novartis Institutes for Biomedical Research, East Hanover, NJ, 07936-1080, USA.
15
Singapore Immunology Network (SIgN), A*STAR, 138648, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 119077, Singapore.
16
Invitrocue Pte Ltd. 138667, Singapore; Mechanobiology Institute, National University of Singapore, 117411, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, 138669, Singapore.
17
Novartis Institute for Tropical Diseases, 138670, Singapore; Singapore Immunology Network (SIgN), A*STAR, 138648, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 119077, Singapore. Electronic address: pablo_bifani@immunol.a-star.edu.sg.

Abstract

Hypnozoites are the liver stage non-dividing form of the malaria parasite that are responsible for relapse and acts as a natural reservoir for human malaria Plasmodium vivax and P. ovale as well as a phylogenetically related simian malaria P. cynomolgi. Our understanding of hypnozoite biology remains limited due to the technical challenge of requiring the use of primary hepatocytes and the lack of robust and predictive in vitro models. In this study, we developed a malaria liver stage model using 3D spheroid-cultured primary hepatocytes. The infection of primary hepatocytes in suspension led to increased infectivity of both P. cynomolgi and P. vivax infections. We demonstrated that this hepatic spheroid model was capable of maintaining long term viability, hepatocyte specific functions and cell polarity which enhanced permissiveness and thus, permitting for the complete development of both P. cynomolgi and P. vivax liver stage parasites in the infected spheroids. The model described here was able to capture the full liver stage cycle starting with sporozoites and ending in the release of hepatic merozoites capable of invading simian erythrocytes in vitro. Finally, we showed that this system can be used for compound screening to discriminate between causal prophylactic and cidal antimalarials activity in vitro for relapsing malaria.

KEYWORDS:

Cellusponge; Hepatocytes culture; Plasmodium cynomolgi; Plasmodium vivax; Radical cure; Spheroids

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