Uptake and metabolism of arginine impact Plasmodium development in the liver

Abstract

Prior to infecting erythrocytes and causing malaria symptoms, Plasmodium parasites undergo an obligatory phase of invasion and extensive replication inside their mammalian host’s liver cells that depends on the parasite’s ability to obtain the nutrients it requires for its intra-hepatic growth and multiplication. Here, we show that L-arginine (Arg) uptake through the host cell’s SLC7A2-encoded transporters is essential for the parasite’s development and maturation in the liver. Our data suggest that the Arg that is taken up is primarily metabolized by the arginase pathway to produce the polyamines required for Plasmodium growth. Although the parasite may hijack the host’s biosynthesis pathway, it relies mainly upon its own arginase-AdoMetDC/ODC pathway to acquire the polyamines it needs to develop. These results identify for the first time a pivotal role for Arg-dependent polyamine production during Plasmodium’s hepatic development and pave the way to the exploitation of strategies to impact liver infection by the malaria parasite through the modulation of Arg uptake and polyamine synthesis.

Alterations in Phosphorylation of Hepatocyte Ribosomal Protein S6 Control Plasmodium Liver Stage Infection

“…RPS6 phosphorylation has been linked to cell size and proliferation (Pende et al, 2000; Ruvinsky et al, 2005), clearance of apoptotic cells (Jeon et al, 2008), and protection against DNA damage in cancerous cells (Khalaileh et al, 2013; Wittenberg et al, 2016). RPS6 has also been linked to regulation of free amino-acid levels (Ruvinsky and Meyuhas, 2006), glucose homeostasis (Pende et al, 2000; Ruvinsky et al, 2005), and lipid biosynthesis (Calvisi et al, 2011), all of which are important for parasite growth (Itani et al, 2014; Itoe et al, 2014; Meireles et al, 2017). …”

Parasite Sensing of Host Nutrients and Environmental Cues

“…Therefore, perturbations of aa metabolism likely shape the outcome of infection. As an example, depletion of arginine prevents the development of Plasmodium berghei liver stages (Dowling et al, 2010;Meireles et al, 2017;Nagaraj et al, 2015;Olszewski et al, 2009) and induces switching from the replicative Toxoplaxma gondii tachyzoites to a slow-growing bradyzoite cyst (Fox et al, 2004). Lipids Lipid profiles are probably the best-characterized infectionassociated metabolic alteration, and several studies have addressed the dependency of parasites on this host resource.…”

Transmembrane solute transport in the apicomplexan parasite Plasmodium

“…[78,79]) and liver stages of Plasmodium development (e.g. [80][81][82]) and further studies are warranted. In addition, there remains the open question of the involvement of host transporters in the altered permeability of host erythrocytes, following Plasmodium infection.…”