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Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model

Genes & Immunity volume 5, pages 168–175 (2004)Cite this article

Abstract

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 (Pklr269A) 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.

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Acknowledgements

We are indebted to Dr Emil Skamene (McGill University Health Center) and Emerillon Therapeutics Inc. for providing AcB55 and AcB61 recombinant congenic strains. This work was supported by research grants from Burroughs Wellcome Fund and the Canadian Institutes of Health Research (CIHR) to MMS and PG and the Canadian Genetic Disease Network to PG. PG is a Distinguished Scientist of the CIHR.

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Author notes

  1. G Min-Oo and A Fortin: Both these authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, McGill University, Montreal, Quebec, Canada

    G Min-Oo & P Gros

  2. Centre for the Study of Host Resistance, McGill University, The Research Institute of McGill University Health Centre, Montreal, Quebec, Canada

    G Min-Oo, M-F Tam, P Gros & MM Stevenson

  3. Emerillon Therapeutics Inc., Montreal, Quebec, Canada

    A Fortin

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  1. G Min-Oo
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  2. A Fortin
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  3. M-F Tam
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  4. P Gros
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  5. MM Stevenson
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Correspondence to P Gros.

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Min-Oo, G., Fortin, A., Tam, MF. et al. Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model. Genes Immun 5, 168–175 (2004). https://doi.org/10.1038/sj.gene.6364069

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