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

Abstract

Background Plasmodium vivax is one of the leading causes of malaria worldwide. Infections with this parasite cause diverse clinical manifestations, and recent studies revealed that infections with P. vivax can result in severe and fatal disease. Despite these facts, biological traits of the host response and parasite metabolism during P. vivax malaria are still largely underexplored. Parasitemia is clearly related to progression and severity of malaria caused by P. falciparum, however the effects of parasitemia during infections with P. vivax are not well understood. Results We conducted an exploratory study using a high-resolution metabolomics platform that uncovered significant associations between parasitemia levels and plasma metabolites from 150 patients with P. vivax malaria. Most plasma metabolites were inversely associated with higher levels of parasitemia. Top predicted metabolites are implicated into pathways of heme and lipid metabolism, which include biliverdin, bilirubin, palmitoylcarnitine, stearoylcarnitine, phosphocholine, glycerophosphocholine, oleic acid and omega-carboxytrinor-leukotriene B4. Conclusions The abundance of several plasma metabolites varies according to the levels of parasitemia in patients with P. vivax malaria. Moreover, our data suggest that the host response and/or parasite survival might be affected by metabolites involved in the degradation of heme and metabolism of several lipids. Importantly, these data highlight metabolic pathways that may serve as targets for the development of new antimalarial compounds.

Lipid hijacking: A unifying theme in vector-borne diseases

“…Susceptibility to severe malaria is correlated with decreased levels of eicosanoids, such as prostaglandin E 2 (PGE 2 ) in both P. falciparum - and P. vivax -infected patients ( Perkins et al, 2001 ; Abreu-Filho et al, 2019 ). Studies from P. vivax- infected patients also reveal that parasitemia is significantly associated with metabolites involved in lipid metabolism, an observation that may be tied to their intracellular growth ( Gardinassi et al, 2017 ). Conversely, in a study observing factors associated with pre-existing P. vivax immunity, semi-immune subjects exhibit increased levels of linoleate metabolites compared to naive subjects ( Gardinassi et al, 2018 ).…”

Mining the Human Host Metabolome Toward an Improved Understanding of Malaria Transmission

“…Studies have been done to investigate the metabolic needs of asexually replicating Plasmodium parasites in vitro (Olszewski et al, 2009). Additional studies have focused on metabolites in human blood that are altered during malaria infections (Basant et al, 2010;Pappa et al, 2015;Surowiec et al, 2015;Decuypere et al, 2016;Gardinassi et al, 2017;Uppal et al, 2017;Ghosh et al, 2018;Cordy et al, 2019). This body of work has demonstrated the utility of this tool for identifying a wide range of physiological changes that occur in vertebrate hosts during malaria infection.…”

Distinct amino acid and lipid perturbations characterize acute versus chronic malaria

“…Striking changes in the plasma levels of amines, fatty acids, glycerophospholipids, endocannabinoids, and hemoglobin-related metabolites have been associated with severe P. falciparum malaria in humans (14)(15)(16)(17). Specific metabolic profiles have also characterized chloroquine-resistant and high-parasite-density Plasmodium vivax malaria in humans (18,19). Still, longitudinal studies characterizing the temporal dynamics of plasma metabolites in Plasmodium-infected hosts have been lacking.…”