The response of Plasmodium falciparum to isoleucine withdrawal is dependent on the stage of progression through the intraerythrocytic cell cycle

Kyle Jarrod Mclean,Marcelo Jacobs-Lorena

doi:10.1186/s12936-020-03220-w

Kyle Jarrod Mclean, Marcelo Jacobs-Lorena

Open Access

https://doi.org/10.1186/s12936-020-03220-w

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Abstract

BackgroundA previous study reported that the malaria parasite Plasmodium falciparum enters an altered growth state upon extracellular withdrawal of the essential amino acid isoleucine. Parasites slowed transit through the cell cycle when deprived of isoleucine prior to the onset of S-phase.MethodsThis project was undertaken to study at higher resolution, how isoleucine withdrawal affects parasite growth. Parasites were followed at regular intervals across an extended isoleucine deprivation time course across the cell cycle using flow cytometry.ResultsThese experiments revealed that isoleucine-deprived parasites never exit the cell cycle, but instead continuously grow at a markedly reduced pace. Moreover, slow growth occurs only if isoleucine is removed prior to the onset of schizogony. After S-phase commenced, the parasite is insensitive to isoleucine depletion and transits through the cell cycle at the normal pace.ConclusionsThe markedly different response of the parasite to isoleucine withdrawal before or after the onset of DNA replication is reminiscent of the nutrient-dependent G1 cell cycle checkpoints described in other organisms.

Highlights

A previous study reported that the malaria parasite Plasmodium falciparum enters an altered growth state upon extracellular withdrawal of the essential amino acid isoleucine
Babbitt et al reported that P. falciparum enters a potentially analogous state when deprived of an extracellular source of the essential amino acid isoleucine [12]
As observed by Babbitt et al [12], young rings (~ 6 h post-infection or hpi) washed thoroughly with Phosphate buffered saline (PBS) and transferred to culture medium lacking isoleucine remained at the starting parasitaemia after 72 h, whereas control parasites completed a cell cycle and re-invaded red blood cells over the same time period (Fig. 2a)

Summary

Introduction

A previous study reported that the malaria parasite Plasmodium falciparum enters an altered growth state upon extracellular withdrawal of the essential amino acid isoleucine. While there has yet to be widespread clinical failure, parasite isolates that display delayed clearance, detectable in the blood as ring stages hours after artemisinin therapy, have been referred to as artemisinin resistant [1]. The observation that this resistance phenotype manifests as McLean and Jacobs‐Lorena Malar J (2020) 19:147 a b. Babbitt et al reported that P. falciparum enters a potentially analogous state when deprived of an extracellular source of the essential amino acid isoleucine [12]

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