Amino acid utilization in intraerythrocytic malaria parasites

Abstract

The human malaria parasite Plasmodium falciparum meets most of its amino acid needs through the degradation of host erythrocyte hemoglobin. To do so, it has at least 11 proteases that function in a semi‐ordered pathway in its acidic digestive vacuole. Despite this robust catabolic system, the parasite must acquire isoleucine exogenously, since this amino acid is absent from adult human hemoglobin. When isoleucine is withdrawn from the culture medium of intraerythrocytic P. falciparum, the parasite slows its metabolism and progresses through its developmental cycle at a reduced rate, 40% that of fed parasites. Isoleucine‐starved parasites remain viable for 72 hours and resume rapid growth upon re‐supplementation. Starved parasites progress through the normal transcriptional program at a slowed rate and do not display any apparent stress response. Plasmodium parasites lack a TOR nutrient sensing pathway and have only a rudimentary amino acid starvation‐sensing eukaryotic initiation factor 2α (eIF2α) response that does not influence 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. This finding informs strategies to disrupt nutrient acquisition for drug development against the nefarious malaria parasite.