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Pyruvate kinase deficiency in mice protects against malaria

Nature Genetics volume 35, pages 357–362 (2003)Cite this article

Abstract

The global health impact of malaria is enormous, with an estimated 300–500 million clinical cases and 1 million annual deaths1. In humans, initial susceptibility to infection with Plasmodium species, disease severity and ultimate outcome of malaria (self-healing or lethal) are under complex genetic control. Alleles associated with sickle cell anemia, β-thalassemia and deficiency in glucose-6-phosphate dehydrogenase have a protective effect against malaria and may have been retained by positive selection in areas of endemic malaria2. Likewise, genetic variations in erythrocyte antigens and levels of host cytokines affect type and severity of disease3,4. A mouse model of infection with Plasmodium chabaudi was used to study the genetic component of malaria susceptibility. Segregation analyses in informative F2 crosses derived from resistant C57BL/6J and susceptible A/J, C3H and SJL strains using extent of blood stage replication of the parasite and survival as traits mapped three P. chabaudi resistance (Char) loci on chromosomes 9 (Char1), 8 (Char2) and 17 (Char3, MHC-linked)5,6,7. Recombinant congenic strains AcB55 and AcB61 are unusually resistant to malaria despite carrying susceptibility alleles at Char1 and Char2. Malaria resistance in AcB55 and AcB61 is associated with splenomegaly and constitutive reticulocytosis, is inherited in an autosomal recessive fashion and is controlled by a locus on chromosome 3 (Char4)8. Sequencing of candidate genes from the Char4 region identified a loss-of-function mutation (269T→A, resulting in the amino acid substitution I90N) in the pyruvate kinase gene (Pklr) that underlies the malaria resistance in AcB55 and AcB61. These results suggest that pyruvate kinase deficiency may similarly protect humans against malaria.

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Figure 1: Blood-stage replication of P. chabaudi in AcB55 and AcB61 mice and segregation analysis of reticulocytosis.
Figure 2: Differentially expressed transcripts in the spleens of AcB55 and AcB61 mice.
Figure 3: Linkage mapping of the monogenic trait controlling reticulocytosis in the AcB55 strain.
Figure 4: A mutation in liver- and erythrocyte-specific Pklr causes reticulocytosis in AcB55 and AcB61 mice.
Figure 5: Association of Pklr-I90N with protection against malaria.

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Acknowledgements

The authors are indebted to E. Skamene for providing AcB55 and AcB61 recombinant congenic strains and to J. Woodgett for providing spotted cDNA arrays. This work was supported by research grants to P.G. and M.M.S. from the Canadian Institutes of Health Research and from the Canadian Genetic Diseases Network. Expertise in transcriptional profiling was made possible by the Genome Health Initiative of the National Research Council of Canada. P.G. is supported by a salary award from the CIHR (Distinguished Scientist) and by a James McGill Professorship. G.M. is supported by the Maysie MacSporran Award from the Strategic Training Centre in Infectious Diseases and Autoimmunity of the Center for the Study of Host Resistance Group of McGill University.

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Authors and Affiliations

  1. Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada

    Gundula Min-Oo, Anny Fortin & Philippe Gros

  2. Research Institute of the McGill University Health Center, Montreal General Hospital, 1650 Cedar Ave, Montreal, QC H3G 1A4, Canada

    Mi-Fong Tam & Mary M Stevenson

  3. Biotechnology Research Institute, National Research Council, 6100 Royalmount, Montreal, QC H4P 2R2, Canada

    André Nantel

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Correspondence to Philippe Gros.

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Min-Oo, G., Fortin, A., Tam, MF. et al. Pyruvate kinase deficiency in mice protects against malaria. Nat Genet 35, 357–362 (2003). https://doi.org/10.1038/ng1260

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