The dormancy-like response of Plasmodium falciparum to amino acid starvation
Mclean, Kyle Jarrod
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The frontline antimalarial Artemisinin is decreasing in efficacy across the Greater Mekong Subregion. The study of parasites from this region has led several authors to propose that Plasmodium falciparum may be able to enter state of dormancy— programmed cell cycle arrest—¬as a means of drug resistance. An independent line of reasearch recently described a similar dormancy-like state in vitro when P. falciparum parasites are starved of the essential amino acid isoleucine, raising the possibility that a shared genetic pathway may underlie survival of both starvation and drug treatment. Here, we revisit and expand upon the dormancy-like response of P. falciparum to isoleucine starvation. We have found that the parasite does not exit the cell cycle upon starvation, but instead enters a state of slow growth. This change in growth rate occurs only if isoleucine is removed prior to the onset of S-phase. After DNA replication has begun, the parasite traverses the cell cycle at its normal pace, and only enters slow growth in the next generation; a response reminiscent of the nutrient-dependent G1 cell cycle checkpoints described in other organisms. We have also implicated the P. falciparum ortholog of the RNA Polymerase III repressor Maf1 in maintaining viability of parasites undergoing starvation-induced slow growth. Parasites defective in Maf1 expression fail to shut-down tRNA expression and display decreased growth and survival under a number of growth-limiting treatments. Lastly, we have assayed the ability of an Artemisinin-resistant field isolate to survive long term isoleucine starvation and found that resistant parasites display increased recovery from isoleucine deprivation. Combined, these results suggest that while the parasite may not exit the cell cycle as in the dormancy responses of other organisms, P. falciparum possesses growth regulatory pathways that can affect the parasite's ability to survive growth-retarding treatments, including both amino acid starvation and Artemisinin.