Red-cell ATP depletion and Protection Against P. falciparum Malaria
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Dr. Winslow serves as a consultant for Siemens Diagnostics, and is on the speaker's bureau for GSK and Cubist.
Synopsis: ATP levels are reduced in homozygous PKLR-/- and heterozygous PKLR+/- erythrocytes. Sodium fluoride (NaF) produces ATP depletion in normal erythrocytes. A dose-dependent effect of ATP depletion on inhibition of parasite invasion and enhancement of phagocytosis of erythrocytes infected with ring-stage parasites was observed. A parallel increase in intraerythrocytic ATP levels by means of parasite-derived ATP was also seen.
Source: Ayi K, et al. Adenosine triphosphate depletion of erythrocytes simulates the phenotype associated with pyruvate kinase deficiency and confers protection against Plasmodium falciparum in vitro. J Infect Dis. 2009;200:1289-1299.
Blood was drawn from healthy individuals living in Toronto with normal hemoglobins and from donors who were known to have protein kinase deficiency (PKD), G6PD deficiency, and Beta thalassemia. Decreased ATP levels were observed in PKD and in NaF-treated normal erythrocytes in vitro. NaF had no direct antiparasitic activity. NaF treatment of normal erythrocytes simulated the phenotype associated with PKD, and these treated red blood cells demonstrated relative refractoriness to invasion by P. falciparum. NaF-treated erythrocytes infected by ring-stage parasites were more avidly phagocytosed by macrophages than normal untreated parasitized erythrocytes. Increased parasite-generated ATP was observed after P. falciparum invasion, and may compensate for low levels of ATP in PKD and in NaF-treated cells, thereby facilitating intracellular maturation of the trophozoite. This increase in parasite-generated ATP after invasion was not seen in G6PD deficient and thalassemic erythrocytes. PfPyrK (a P. falciparum pyruvate kinase) gene expression was shown to correlate with ATP levels in parasitized erythrocytes.
Commentary
This study is the first to show that ATP depletion (and secondarily increased production of 2,3-DPG with a variety of downstream effects resulting in red cell membrane destabilization) is the mechanism underlying PKD-associated protection against P. falciparum malaria. These membrane effects impair parasite invasion and, by increased IgG and C3c binding to the damaged red cell membrane, also enhance monocyte-mediated phagocytosis of ring-stage parasitized erythrocytes.
The high prevalence of hemoglobinopathies and red-cell enzyme deficiencies (which presumably resulted from selective evolutionary pressure) in human populations who live in malaria-endemic areas has long fascinated clinicians. This study sheds some light on the mechanism likely responsible for the protective effect of PKD against infection with P. falciparum.
Blood was drawn from healthy individuals living in Toronto with normal hemoglobins and from donors who were known to have protein kinase deficiency (PKD), G6PD deficiency, and Beta thalassemia.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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