Abstract
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.
Highlights
Plasmodium vivax (P. vivax) is the major cause of malaria outside of Africa with an estimated 13.8 million malaria cases globally in 2015 (World Health Organization (WHO), 2015)
While previous reports have emerged providing a first glance of gene expression in Plasmodium liver stages (Cubi et al, 2017; Vaughan et al, 2009), we provide here a comprehensive dataset derived from green fluorescent protein (GFP)-tagged Plasmodium cynomolgi (P. cynomolgi) (Voorberg-van der Wel et al, 2013) — the nonhuman primate sister taxon of P. vivax, known to form hypnozoites (Dembeleet al., 2014; Krotoski et al, 1982)
To quantify parasite-specific expression for each P. cynomolgi gene, we determined the number of sequencing reads aligned to genes and computed gene expression values as the number of Fragments Per Kilobase per Million fragments mapped (FPKM) (Schuierer and Roma, 2016)
Summary
Plasmodium vivax (P. vivax) is the major cause of malaria outside of Africa with an estimated 13.8 million malaria cases globally in 2015 (World Health Organization (WHO), 2015). In vitro hepatic cultures systems for hypnozoite-forming parasites have been developed (March et al, 2013; Zeeman et al, 2014) and rodent models of humanized liver stage infections constituted recent advances (Mikolajczak et al, 2015), the search for new drugs targeting hypnozoites is hampered by our limited knowledge of this enigmatic dormant stage. Microbes commonly employ cellular quiescence to survive environmental stresses such as starvation, immune surveillance, or chemotherapeutic interventions and for disease causing microbes, dormancy often underlies chronic infections that considerably complicate the clinical management of infected patients (Rittershaus et al, 2013). Cellular quiescence generally requires a physiological response underscored by a global repression of cellular metabolism but the preservation of mitochondrial respiration for ATP homeostasis and the maintenance of genome integrity (Rittershaus et al, 2013).
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