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Nat Commun. 2018 May 9;9(1):1837. doi: 10.1038/s41467-018-04221-9.

A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum.

Author information

1
Department of Global Health, College of Public Health, Center for Global Health and Infectious Diseases Research, University of South Florida, 3720 Spectrum Blvd 404, Tampa, FL, 33612, USA.
2
Center for Tropical and Emerging Global Diseases, University of Georgia, 500 DW Brooks Dr. Suite 370, Athens, GA, 30602, USA.
3
Department of Entomology, Armed Forces Research Institute of Medical Sciences (AFRIMS), 315/6 Rajvithi Rd, Bangkok, 10400, Thailand.
4
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
5
Shoklo Malaria Research Unit, Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, 68/30 Bantung Rd, Mae Sot, Tak, 63110, Thailand.
6
Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.
7
Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, 5 Boulevard Monivong-PO Box 983, Phnom Penh, 12 201, Cambodia.
8
California Institute for Biomedical Research (Calibr), 11119N. Torrey Pines Rd, Suite 100, La Jolla, CA, 92037, USA.
9
Medicines for Malaria Venture, Pré-Bois Rd 20, Meyrin, 1215, Switzerland.
10
Center for Infectious Disease Research, 307 Westlake Ave N Suite 500, Seattle, WA, 98109, USA.
11
Department of Global Health, College of Public Health, Center for Global Health and Infectious Diseases Research, University of South Florida, 3720 Spectrum Blvd 404, Tampa, FL, 33612, USA. jadams3@health.usf.edu.

Abstract

Malaria liver stages represent an ideal therapeutic target with a bottleneck in parasite load and reduced clinical symptoms; however, current in vitro pre-erythrocytic (PE) models for Plasmodium vivax and P. falciparum lack the efficiency necessary for rapid identification and effective evaluation of new vaccines and drugs, especially targeting late liver-stage development and hypnozoites. Herein we report the development of a 384-well plate culture system using commercially available materials, including cryopreserved primary human hepatocytes. Hepatocyte physiology is maintained for at least 30 days and supports development of P. vivax hypnozoites and complete maturation of P. vivax and P. falciparum schizonts. Our multimodal analysis in antimalarial therapeutic research identifies important PE inhibition mechanisms: immune antibodies against sporozoite surface proteins functionally inhibit liver stage development and ion homeostasis is essential for schizont and hypnozoite viability. This model can be implemented in laboratories in disease-endemic areas to accelerate vaccine and drug discovery research.

PMID:
29743474
PMCID:
PMC5943321
DOI:
10.1038/s41467-018-04221-9
[Indexed for MEDLINE]
Free PMC Article

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