Host Reticulocytes Provide Metabolic Reservoirs That Can Be Exploited by Malaria Parasites

Abstract

Human malaria parasites proliferate in different erythroid cell types during infection. Whilst Plasmodium vivax exhibits a strong preference for immature reticulocytes, the more pathogenic P. falciparum primarily infects mature erythrocytes. In order to assess if these two cell types offer different growth conditions and relate them to parasite preference, we compared the metabolomes of human and rodent reticulocytes with those of their mature erythrocyte counterparts. Reticulocytes were found to have a more complex, enriched metabolic profile than mature erythrocytes and a higher level of metabolic overlap between reticulocyte resident parasite stages and their host cell. This redundancy was assessed by generating a panel of mutants of the rodent malaria parasite P. berghei with defects in intermediary carbon metabolism (ICM) and pyrimidine biosynthesis known to be important for P. falciparum growth and survival in vitro in mature erythrocytes. P. berghei ICM mutants (pbpepc-, phosphoenolpyruvate carboxylase and pbmdh-, malate dehydrogenase) multiplied in reticulocytes and committed to sexual development like wild type parasites. However, P. berghei pyrimidine biosynthesis mutants (pboprt-, orotate phosphoribosyltransferase and pbompdc-, orotidine 5′-monophosphate decarboxylase) were restricted to growth in the youngest forms of reticulocytes and had a severe slow growth phenotype in part resulting from reduced merozoite production. The pbpepc-, pboprt- and pbompdc- mutants retained virulence in mice implying that malaria parasites can partially salvage pyrimidines but failed to complete differentiation to various stages in mosquitoes. These findings suggest that species-specific differences in Plasmodium host cell tropism result in marked differences in the necessity for parasite intrinsic metabolism. These data have implications for drug design when targeting mature erythrocyte or reticulocyte resident parasites.

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

“…Deletion of KDH in the insect-transmissible NF54 strain of P. falciparum [36], and SDH [43], NDH [44], ATP synthase [31], or BCKDH [46] in P. berghei, all result in failure of normal post-fertilization progression to ookinetes and/or oocysts, although viable gametes are apparently formed. A similar phenotype is observed in P. berghei PEP carboxylase mutants [51]. Interestingly, deletion or chemical inhibition of cis-aconitase (Aco, responsible for conversion of citrate to isocitrate) in P. falciparum results in an earlier failure in sexual development, with these cells being unable to develop beyond stage III gametocytes [26,36].…”

“…the ability to scavenge from the more[ 1 7 _ T D $ D I F F ] complex, nutrient-replete metabolome of the developing, immature blood cell forms [51].…”

“…This includes differentiation of gametes into ookinetes, invasion of the mid-gut epithelium, oocyst formation, and, ultimately, differentiation into sporozoites [77,78]. The increased reliance on the TCA is supported by upregulation of TCA enzymes in gametocyte stages [79,80] and the profound physiological consequences of genetic disruption and/or chemical inhibition of these enzymes (Figure 1) [26,31,36,43,44,46,51,62,81].…”

Metabolome-wide association study of peripheral parasitemia in Plasmodium vivax malaria

“…P. falciparum ’s blood-stages invade and replicate inside of red blood cells (RBCs) at any age, whereas P. vivax preferentially targets reticulocytes (immature erythrocytes that typically comprise about 1–2% of circulating RBCs) (Lim et al, 2016). A recent study demonstrated that reticulocytes exhibit a more complex metabolic phenotype than mature erythrocytes, suggesting that Plasmodium host cell tropism of distinct species may be caused by differences in the parasite’s intrinsic metabolism (Srivastava et al, 2015). The P. vivax preference for reticulocytes contributes to lower parasitemias, which likely accounts for slower progression of the disease and reduced lethality rates of P. vivax malaria when compared with P. falciparum (Anstey et al, 2012; Howes et al, 2016; Mueller et al, 2009).…”

Inhibition of Glutathione Biosynthesis Sensitizes Plasmodium berghei to Antifolates

“…Other possible explanations why ␥-gcs is nonessential in P. berghei include (i) P. berghei can upregulate other antioxidant pathways, such as thioredoxin and plasmoredoxin pathways, to compensate for the loss of ␥-gcs, while P. falciparum cannot, and (ii) the difference between the cellular tropisms of P. falciparum and P. berghei. P. falciparum infects mature erythrocytes, while P. berghei infects reticulocytes, which contain richer metabolites and higher antioxidant levels than mature erythrocytes (33). Therefore, P. berghei might live in a friendlier environment than P. falciparum, resulting in the ability of ⌬gcs P. berghei to survive while ⌬gcs P. falciparum cannot.…”