How Malaria Parasites Acquire Nutrients From Their Host

Abstract

Plasmodium parasites responsible for the disease malaria reside within erythrocytes. Inside this niche host cell, parasites internalize and digest host hemoglobin to source amino acids required for protein production. However, hemoglobin does not contain isoleucine, an amino acid essential for Plasmodium growth, and the parasite cannot synthesize it de novo. The parasite is also more metabolically active than its host cell, and the rate at which some nutrients are consumed exceeds the rate at which they can be taken up by erythrocyte transporters. To overcome these constraints, Plasmodium parasites increase the permeability of the erythrocyte membrane to isoleucine and other low-molecular-weight solutes it requires for growth by forming new permeation pathways (NPPs). In addition to the erythrocyte membrane, host nutrients also need to cross the encasing parasitophorous vacuole membrane (PVM) and the parasite plasma membrane to access the parasite. This review outlines recent advances that have been made in identifying the molecular constituents of the NPPs, the PVM nutrient channel, and the endocytic apparatus that transports host hemoglobin and identifies key knowledge gaps that remain. Importantly, blocking the ability of Plasmodium to source essential nutrients is lethal to the parasite, and thus, components of these key pathways represent potential antimalaria drug targets.

Keywords: Plasmodium; malaria; new permeation pathway; nutrients; transporters.

FIGURE 1

Lifecycle of Plasmodium falciparum. P. falciparum parasites are injected into a human host via mosquito bites (a) where they then travel to the liver (b). After parasite replication, merozoites are released into the blood where they invade erythrocytes to commence the asexual replication cycle (c). Parasites develop within the erythrocyte in distinct forms (ring, trophozoite, and schizont) until erythrocyte lysis occurs, releasing merozoites for reinvasion.

FIGURE 2

Nutrient acquisition by P. falciparum relies on membrane transporters and the cytostome. Upon infection by Plasmodium parasites, erythrocytes are extensively remodeled to accommodate the growing parasite. The parasite, contained by its own PPM, is encased within a parasitophorous vacuole (PV) and a PV membrane (PVM). Each membrane in the infected erythrocyte, including the erythrocyte plasma membrane (EPM), is modified to include transporters that enable the parasite to access nutrients from its host. These include the NPPs at the EPM, the nutrient channel at the PVM, and transporters at the PPM, whereas hemoglobin uptake and transport to the food vacuole occur via the cytostome. The NPP channel is proposed to be a CLAG3 dimer/oligomer that associates with RhopH2 and RhopH3. Alternatively, CLAG3, RhopH2, and RhopH3 may activate an endogenous host channel. The contribution of other parasite-encoded channels to the NPPs such as the calcium-dependent, stress-gated ion channel (CSC), and OMPP is unknown; the localization of both of these proteins is yet to be ascertained. The nutrient channel at the PVM comprises EXP2, with EXP1 being critical for proper distribution of the EXP2 nutrient channel. EXP2 also forms the pore of the translocon of exported proteins (PTEX). RON3 is implicated in both nutrient uptake across the PVM and protein export with an unknown function. The PPM is also decorated with a raft of transporters that facilitate the uptake of diverse substrates to satisfy the metabolic requirements of the growing parasite.