The Plasmodium Liver-Specific Protein 2 (LISP2) is an early marker of liver stage development
Abstract
Plasmodium vivax hypnozoites persist in the liver, cause malaria relapse and represent a major challenge to malaria elimination. Our previous transcriptomic study provided a novel molecular framework to enhance our understanding of the hypnozoite biology (Voorberg-van der Wel A, et al., 2017). In this dataset, we identified and characterized the Liver-Specific Protein 2 (LISP2) protein as an early molecular marker of liver stage development. Immunofluorescence analysis of hepatocytes infected with relapsing malaria parasites, in vitro (P. cynomolgi) and in vivo (P. vivax), reveals that LISP2 expression discriminates between dormant hypnozoites and early developing parasites. We further demonstrate that prophylactic drugs selectively kill all LISP2 positive parasites, while LISP2 negative hypnozoites are only sensitive to anti-relapse drug tafenoquine. Our results provide novel biological insights in the initiation of liver stage schizogony and an early marker suitable for the development of drug discovery assays predictive of anti-relapse activity.
Data availability
All data generated during the study are submitted as supplementary source files.
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Malaria Liver Stages TranscriptomeNCBI Sequence Read Archive, SRP096160.
Article and author information
Author details
Funding
Bill and Melinda Gates Foundation (OPP1141292)
- Guglielmo Roma
- Clemens H M Kocken
- Thierry Tidiane Diagana
Bill and Melinda Gates Foundation (OPP1137694)
- Sebastian A Mikolajczak
Funders have no role in the design of the study.
Ethics
Animal experimentation: Ethics statement included in the method section of the manuscript.
Copyright
© 2019, Gupta et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Microbiology and Infectious Disease
eLife has recently published a wide range of papers on malaria, covering a diversity of themes including parasite biology, epidemiology, immunology, drugs and vaccines.
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- Microbiology and Infectious Disease
Plasmodium sporozoites are inoculated into the skin during the bite of an infected mosquito. This motile stage invades cutaneous blood vessels to reach the liver and infect hepatocytes. The circumsporozoite protein (CSP) on the sporozoite surface is an important antigen targeted by protective antibodies (Abs) in immunoprophylaxis or elicited by vaccination. Antibody-mediated protection mainly unfolds during parasite skin migration, but rare and potent protective Abs additionally neutralize sporozoite in the liver. Here, using a rodent malaria model, microscopy and bioluminescence imaging, we show a late-neutralizing effect of 3D11 anti-CSP monoclonal antibody (mAb) in the liver. The need for several hours to eliminate parasites in the liver was associated with an accumulation of 3D11 effects, starting with the inhibition of sporozoite motility, sinusoidal extravasation, cell invasion, and terminating with the parasite killing inside the invaded cell. This late-neutralizing activity could be helpful to identify more potent therapeutic mAbs with stronger activity in the liver.