title: 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 We report that when isoleucine is withdrawn from the culture medium of intraerythrocytic P. falciparum, the parasite slows its metabolism and progresses through its developmental cycle at a reduced rate.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.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Shalon E
authors.initials: SE
authors.lastname: Babbitt
authors.forename: Lindsey
authors.initials: L
authors.lastname: Altenhofen
authors.forename: Simon A
authors.initials: SA
authors.lastname: Cobbold
authors.forename: Eva S
authors.initials: ES
authors.lastname: Istvan
authors.forename: Clare
authors.initials: C
authors.lastname: Fennell
authors.forename: Christian
authors.initials: C
authors.lastname: Doerig
authors.forename: Manuel
authors.initials: M
authors.lastname: Llinás
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D037621:Artemisinins / Q000494:pharmacology; D002244:Carbon / Q000378:metabolism; D020717:Eukaryotic Initiation Factor-2B / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D017125:Genes, Protozoan / Q000235:genetics; D006605:Hibernation / Q000187:drug effects; D006801:Humans; D007532:Isoleucine / Q000172:deficiency*; D055442:Metabolome / Q000187:drug effects; D010271:Parasites / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D010447:Peptide Hydrolases / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D015800:Protozoan Proteins / Q000378:metabolism; D013217:Starvation
chemical_list: D037621:Artemisinins; D020717:Eukaryotic Initiation Factor-2B; D015800:Protozoan Proteins; D007532:Isoleucine; D002244:Carbon; D010447:Peptide Hydrolases