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.
Subject(s)
Malaria, Vivax/genetics , Plasmodium cynomolgi/genetics , Plasmodium vivax/genetics , Protozoan Proteins/genetics , Aminoquinolines/pharmacology , Animals , Antimalarials/pharmacology , Biomarkers/metabolism , Biomarkers, Pharmacological , Hepatocytes/metabolism , Hepatocytes/parasitology , Host-Parasite Interactions/genetics , Humans , Liver/drug effects , Liver/parasitology , Macaca mulatta/genetics , Macaca mulatta/parasitology , Malaria, Vivax/drug therapy , Malaria, Vivax/parasitology , Plasmodium cynomolgi/parasitology , Plasmodium vivax/drug effects , Plasmodium vivax/pathogenicity , Protozoan Proteins/metabolism , Sporozoites/genetics , Transcriptome/drug effectsABSTRACT
Plasmodium liver hypnozoites, which cause disease relapse, are widely considered to be the last barrier towards malaria eradication. The biology of this quiescent form of the parasite is poorly understood which hinders drug discovery. We report a comparative transcriptomic dataset of replicating liver schizonts and dormant hypnozoites of the relapsing parasite Plasmodium cynomolgi. Hypnozoites express only 34% of Plasmodium physiological pathways, while 91% are expressed in replicating schizonts. Few known malaria drug targets are expressed in quiescent parasites, but pathways involved in microbial dormancy, maintenance of genome integrity and ATP homeostasis were robustly expressed. Several transcripts encoding heavy metal transporters were expressed in hypnozoites and the copper chelator neocuproine was cidal to all liver stage parasites. This transcriptomic dataset is a valuable resource for the discovery of vaccines and effective treatments to combat vivax malaria.
