Plasmodium's fight for survival: escaping elimination while acquiring nutrients

Abstract

Plasmodium parasites extensively alter their host hepatocyte to evade host detection and support an unprecedented replication rate. Host cell manipulation includes association with the host early and late endomembrane systems, where Plasmodium accesses nutrients while suppressing cellular immune processes. Early endomembrane organelles provide an opportunity to sequester an abundance of lipids and proteins, but the association with late endomembrane organelles also risks autophagy-mediated elimination. While not all parasites survive, those that do benefit from a plethora of nutrients provided through this pathway. In this review, we discuss recent advances in our understanding of how Plasmodium parasites balance the need for host nutrients while avoiding elimination during the liver stage.

Keywords: Plasmodium; autophagy; endomembrane; hepatocyte; lipids; malaria.

Figure 1.. Plasmodium restructures the early endomembrane system and induces the unfolded protein response.

After invasion, Plasmodium localizes next to the host nucleus where the host endoplasmic reticulum (ER) and Golgi surround the parasitophorous vacuole membrane (PVM). Parasite-induced fragmentation and contact with the host Golgi correlates with parasite survival. Host proteins involved in anterograde vesicle trafficking (RAB1A, CERT1A, GGA1, and RAB11A), retrograde vesicle trafficking (VPS51, ARF1, and COPI), and intra-Golgi vesicle trafficking (ARF1 and CERT1) are essential for parasite viability. Liver stage (LS) development is supported by the host unfolded protein response (UPR). The UPR is predicted to aid in immune evasion by inhibiting the transporter associated with antigen processing- (TAP)-dependent antigen presentation and in nutrient acquisition by upregulating host lipid synthesis and inhibiting iron export by suppressing the exporter ferroportin. Concurrently, the iron importer divalent metal transporter-1 (DMT1) is known to be upregulated during Plasmodium infection, increasing intracellular iron levels. Abbreviation: PV, parasitophorous vacuole.

Figure 2.. Summary of LC3 incorporation into different autophagy pathways.

AMP-activated protein kinase (AMPK) activates while mechanistic target of rapamycin (mTOR) suppresses canonical autophagy. Autophagosome formation requires the ULK1 and PI3K complexes, along with the ATG5, ATG12, and ATG16L complex, to lipidate and incorporate LC3-II into the double membrane. Selective and canonical autophagy use the double-membrane autophagosome while LC3-associated phagocytosis and Plasmodium-associated autophagy-related response directly incorporate LC3 into the membrane. The table summarizes autophagy-related proteins (highlighted in red) that have been investigated for their role in Plasmodium LS infection. (See [66,67,76,77].) Abbreviations: PV, parasitophorous vacuole; PVM, parasitophorous vacuole membrane.

Figure 3.. Host late endomembrane remodeling and nutrient acquisition during Plasmodium infection of hepatocytes.

Before invasion, Plasmodium secretes an unknown sporozoite factor that causes lysosomes to redistribute to the cell periphery. It is hypothesized that Plasmodium may invade the host cell through a lysosomal exocytosis event. (A) During invasion, lysosomes and late endosomes surround the sporozoite and decorate the parasitophorous vacuole membrane (PVM) with LC3, ubiquitin, p62/Sequestosome (SQSTM1), neighbor of BRCA1 (NBR1), and nuclear dot protein 52 (NDP52). (B) During schizogony, Plasmodium interacts with lysosomes/late endosomes/amphisomes to acquire nutrients required for replication. Arrows surrounding lysosomes/late endosomes/amphisomes indicate mechanisms to deliver nutrients through direct fusion or kiss-and-run fusion events. To avoid lysosomal fusion and elimination, Plasmodium sheds LC3 and lysosomes to the TVN and host cytosol. Abbreviations: PV, parasitophorous vacuole; TVN, tubovesicular network.

Figure 4.. Plasmodium associates to the hepatocyte bile canaliculus and recruits host lipids.

The bile canalicular network forms at the apical domain of adjacent hepatocytes, and Plasmodium preferentially localizes to this region. Cholesterol from the host cell membrane is incorporated into the parasitophorous vacuole membrane (PVM) during invasion and later sourced from both extracellular low-density lipoprotein (LDL) and the mevalonate pathway. Further, late endosomes (marked with LAMP2 and NPC) associated with the PVM and interactions between the host ApoH and parasite EXP-1 could support cholesterol transport. Phosphatidylcholine is found in the PVM, parasite plasma membrane, and within the parasitophorous vacuole (PV). Host L-FABP and parasite UIS3 protein–protein interactions could facilitate the passage of long-chain fatty acids from the host to the parasite.