Plasmodium falciparum responds to amino acid starvation by entering into a hibernatory state

Abstract

The human malaria parasite Plasmodium falciparum is auxotrophic for most amino acids. Its amino acid needs are met largely through the degradation of host erythrocyte hemoglobin; however the parasite must acquire isoleucine exogenously, because this amino acid is not present in adult human hemoglobin. We report that when isoleucine is withdrawn from the culture medium of intraerythrocytic P. falciparum, the parasite slows its metabolism and progresses through its developmental cycle at a reduced rate. Isoleucine-starved parasites remain viable for 72 h and resume rapid growth upon resupplementation. Protein degradation during starvation is important for maintenance of this hibernatory state. Microarray analysis of starved parasites revealed a 60% decrease in the rate of progression through the normal transcriptional program but no other apparent stress response. Plasmodium parasites do not possess a TOR nutrient-sensing pathway and have only a rudimentary amino acid starvation-sensing eukaryotic initiation factor 2α (eIF2α) stress response. Isoleucine deprivation results in GCN2-mediated phosphorylation of eIF2α, but kinase-knockout clones still are able to hibernate and recover, indicating that this pathway does not directly promote survival during isoleucine starvation. We conclude that P. falciparum, in the absence of canonical eukaryotic nutrient stress-response pathways, can cope with an inconsistent bloodstream amino acid supply by hibernating and waiting for more nutrient to be provided.protease | artemesinin | autophagy

A genomic and evolutionary approach reveals non-genetic drug resistance in malaria

“…Much previous work in P. falciparum amino acid homeostasis has focused on the partially conserved amino acid starvation pathway [23,43,44], which results in translational inhibition and a hibernation-like state [44]. We believe that this stable non-genetic resistance is not an immediate starvation response, but a re-regulation of metabolism.…”

“…Babbit et al . [44] saw no difference in either proline or isoleucine levels between isoleucine-fed and isoleucine-starved parasites. Based on temporality and amino acid homeostatic concentrations, we thus posit that halofuginone-induced resistance represents a separate biological phenomenon resulting in long-term upregulation of proline homeostasis.…”

Host-mediated impairment of parasite maturation during blood-stage Plasmodium infection

“…However, there are a number of precedents for altered Plasmodium life-cycle kinetics in vitro and in vivo. In vitro, for example, reduced availability of isoleucine has been shown to slow the maturation rate of P. falciparum, which has been estimated to have a 60% decrease in the rate of maturation through the parasite life cycle (27). This suggests that deprivation of nutrients could theoretically slow parasite development in vivo.…”

Do hypnozoites cause relapse in malaria?

“…The cell biological etiology of drug-associated P. falciparum quiescence is unknown, but it would seem that the mechanisms involved for drug-related dormancy might not be the same as for parasite starvation-associated quiescence [65]. Important advances in understanding the mechanistic basis of artemisinin-parasite interaction outcomes have recently been made [66][67][68].…”