Abstract
Mechanisms of malaria parasite interaction with its host red blood cell may provide potential targets for new antimalarial approaches. Pyruvate kinase deficiency has been associated with resistance to malaria in both experimental models and population studies. Two of the major pyruvate kinase deficient-cell disorders are the decrease in ATP and the increase in 2,3-biphosphoglycerate (2,3-BPG) concentration. High levels of this metabolite, only present in mammalian red blood cell, has an inhibitory effect on glycolysis and we hypothesized that its accumulation may also be harmful to the parasite and be involved in the mechanism of protection provided by that enzymopathy. We examined the effect of a synthetic form, 2,3-DPG, on the Plasmodium falciparum intraerythrocytic developmental cycle in vitro. Results showed an impairment of parasite growth with a direct effect on parasite maturation as significant lower progeny emerged from parasites that were submitted to 2,3-DPG. Further, adding the compound to the culture medium did not result in any effect on the host cell, but instead the metabolic profile of an infected cell became closer to that of a non-infected cell.
Highlights
Nowadays, together with COVID-19, malaria is a major public and global health problem, which accounted for 241 million cases and 627 000 deaths in 2020 (World Health Organization, 2021)
2.3.1 Red Blood Cells red blood cell (RBC) were incubated in triplicate in a 96 well U-bottom microplate for 0, 30, 60 and 90 minutes with 2,3-DPG in 0.9% NaCl according to a two-fold serial dilution, following an adapted protocol from de Freitas et al (2008) and Evans et al (2013)
Five experimental groups were simultaneously analyzed in the invasion/maturation assay: 1) RBCs incubated for 24 hours with 2,3-DPG 8mM prior to infection and put in culture conditions, 2) infected RBCs incubated with 2,3-DPG 8mM added every 24 hours to culture medium after infection, 3) and 4) two different infected NaF-inducible Pyruvate kinase deficiency (PKD) RBCs described above, and 5) a control group with infected RBCs in cRPMI alone
Summary
Together with COVID-19, malaria is a major public and global health problem, which accounted for 241 million cases and 627 000 deaths in 2020 (World Health Organization, 2021). Malaria has been one of the strongest selective forces on the human genome, selecting host variants and cellular mechanisms that are determinant for parasite survival, influence pathogenesis and may protect against infection or disease severity (Kariuki and Williams, 2020). PKD was associated with resistance to malaria (Min-Oo et al, 2003; Laroque et al, 2017) and babesiosis (Oka et al, 2008) in rodent models and in in vitro cultures of P. falciparum using human PK-deficient RBC (Ayi et al, 2008; Durand and Coetzer, 2008). This association has been corroborated by population studies (Alves et al, 2010; Machado et al, 2010; Machado et al, 2012). We compared the metabolic profiles of infected and non-infected RBCs treated versus not treated with 2,3-DPG
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