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Malaria that is caused by Plasmodium falciparum is a significant global health problem. Genetic characteristics of the host influence the severity of disease and the ultimate outcome of infection, and there is evidence of coevolution of the plasmodium parasite with its host. In humans, pyruvate kinase deficiency is the second most common erythrocyte enzyme disorder. Here, we show that pyruvate kinase deficiency provides protection against infection and replication of P. falciparum in human erythrocytes, raising the possibility that mutant pyruvate kinase alleles may confer a protective advantage against malaria in human populations in areas where the disease is endemic., (Copyright 2008 Massachusetts Medical Society.)

AcB55, AcB61 and CBA/N-Pk(slc) mice carry loss of function mutations in the erythrocyte specific pyruvate kinase gene (Pklr). In AcB55 and AcB61 (Pklr(I90N)) PK deficiency is protective against blood-stage malaria. The mechanistic basis of protection against malaria is unknown and was studied in these two mutant alleles in vivo. The Pklr(G338D) mutation of the CBA/N-Pk(slc) mutant is shown to be more deleterious than the Pklr(I90N) allele with respect to enzymatic activity and severity of hemolytic anemia, with a more dramatic reduction in the half-life of erythrocytes (increased turnover) in the CBA/N-Pk(slc) mice. The CBA/N-Pk(slc) mice are also shown to be highly resistant to infection with Plasmodium chabaudi AS when compared to CBA/J and CBA/N controls. Resistance to malaria, measured as lower levels of blood-stage replication of P. chabaudi, rapid elimination of infected erythrocytes and increased survival to infection, was greater in the Pklr(G338D) mutant, CBA/N-Pk(slc), than in the Pklr(I90N) mutant strains, AcB55/AcB61. These results strongly suggest a correlation between severity of PK-deficiency and extent of protection against malaria. Additionally, the protective effect is independent of the genetic background on which the Pklr mutations occurred.

The malaria threat to global health is exacerbated by widespread drug resistance in the Plasmodium parasite and its insect vector, and the lack of an efficacious vaccine. Infection with Plasmodium parasites can cause a wide spectrum of pathologies, from a transient mild form of anaemia to a severe and rapidly fatal cerebral disease. Epidemiological studies in humans and experiments in animal models have shown that genetic factors play a key role in the onset, progression, type of disease developed and ultimate outcome of malaria. The protective effect of polymorphic variants in erythrocyte-specific structural proteins or metabolic enzymes against the blood-stage of the disease is one of the clearest illustrations of this genetic modulation, and has suggested co-evolution of the Plasmodium parasite with its human host in areas of endemic disease. Here, we present a brief overview of erythrocyte polymorphisms with biological relevance to malaria pathogenesis, and current work on the mechanism(s) by which these mediate their protective effect. The recent addition of erythrocyte pyruvate kinase to this group of protective genes will also be discussed.

The recombinant congenic mouse strains AcB55 and AcB61 are extremely resistant to malaria (Plasmodium chabaudi AS) despite the presence of susceptibility alleles at the known Char1/Char2 resistance loci. Resistance in AcB55 and AcB61 is controlled by a locus on chromosome 3 (Char4) shown to be allelic with or tightly linked to a loss-of-function mutation in pyruvate kinase (Pklr). AcB55 and AcB61 show important splenomegaly prior to infection caused by the expansion of the red pulp, and display histological signs of extramedullary erythropoiesis in the liver. Examination of splenic cell populations by flow cytometry demonstrates elevated numbers of TER119-positive erythroid precursor cells (>30% of total spleen cells), while RNA expression studies show elevated expression of erythrocyte-specific transcripts such as globin, transferrin receptor, and Nramp2/Slc11a2 in the spleen of both strains. Hematological profiling in both strains is consistent with the presence of anemia as evidenced by low total erythrocyte counts, decreased hemoglobin, as well as abnormally high numbers of circulating reticulocytes (15-20%). These results strongly suggest that the mutant Pklr allele (Pklr(269A)) of AcB55/61 strains causes hemolytic anemia compensated by constitutive erythropoiesis, which in turn protects the mice against P. chabaudi infection. The possible molecular basis of the Pklr protective effect is discussed and is under current investigation in these two strains.