The Plasmodium Liver-Specific Protein 2 (LISP2) is an early marker of liver stage development
- Novartis Institute for Tropical Diseases, United States
- Université des Sciences, des Techniques et des Technologies de Bamako, Mali
- Biomedical Primate Research Centre, Netherlands
- Novartis Institutes for BioMedical Research, Switzerland
- Novartis Institute for Tropical Diseases, Singapore
- Center for Infectious Disease Research, United States
- Mahidol University, Thailand
- Ehime University, Japan
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
Annemarie Voorberg-van der Wel
Jetsumon Sattabongkot
Thierry Tidiane Diagana
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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The Plasmodium Liver-Specific Protein 2 (LISP2) is an early marker of liver stage development
eLife 8:e43362.
https://doi.org/10.7554/eLife.43362
Further reading
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Mycofactocin is a redox cofactor essential for the alcohol metabolism of mycobacteria. While the biosynthesis of mycofactocin is well established, the gene mftG, which encodes an oxidoreductase of the glucose-methanol-choline superfamily, remained functionally uncharacterized. Here, we show that MftG enzymes are almost exclusively found in genomes containing mycofactocin biosynthetic genes and are present in 75% of organisms harboring these genes. Gene deletion experiments in Mycolicibacterium smegmatis demonstrated a growth defect of the ∆mftG mutant on ethanol as a carbon source, accompanied by an arrest of cell division reminiscent of mild starvation. Investigation of carbon and cofactor metabolism implied a defect in mycofactocin reoxidation. Cell-free enzyme assays and respirometry using isolated cell membranes indicated that MftG acts as a mycofactocin dehydrogenase shuttling electrons toward the respiratory chain. Transcriptomics studies also indicated remodeling of redox metabolism to compensate for a shortage of redox equivalents. In conclusion, this work closes an important knowledge gap concerning the mycofactocin system and adds a new pathway to the intricate web of redox reactions governing the metabolism of mycobacteria.
