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Escape from Malaria — The Pyruvate Kinase Connection

Pyruvate kinase deficiency protects against Plasmodium falciparum infection in erythrocytes by two different mechanisms.

Previous genetic studies examining the susceptibility of mice to malaria demonstrated that animals with a mutation in the gene for pyruvate kinase (PK), Pklr, were resistant to infection with a challenge Plasmodium strain. Now, investigators in Canada are seeking to determine the molecular basis of this protective effect.

Five patients with homozygous (n=3) or heterozygous (n=2) PK deficiency provided erythrocytes for in vitro assays to evaluate both parasite invasion of erythrocytes and phagocytosis of erythrocytes by monocytes collected from healthy donors. These five patients were screened and did not have other hemolytic disorders. Assay comparisons included erythrocytes collected from individuals (controls) who did not have PK deficiency.

Compared with erythrocytes from controls, those from participants with homozygous PK deficiency showed lower levels of invasion by Plasmodium falciparum during three consecutive growth cycles (P=0.01, P<0.001, and P<0.001 for the first, second, and third cycles, respectively). Levels of invasion did not differ significantly between erythrocytes from participants with heterozygous PK deficiency and those from controls.

Phagocytic uptake of ring-stage–infected erythrocytes was greater for erythrocytes from participants who were homozygous (P<0.001) or heterozygous (P=0.003) for the PKLR mutation than for erythrocytes from controls. Additional investigation indicated that the mechanism involved in increased phagocytosis was C3c-mediated.

Comment: These findings together with results from previous murine infection models suggest that PK deficiency can confer protection against malaria. If further study in humans confirms these preliminary findings and leads to the development of unique approaches for preventing or treating malaria, the investigators will have provided a perfect example of success in translational research.

— Larry M. Baddour, MD

Published in Journal Watch Infectious Diseases April 16, 2008

Citation(s):

Ayi K et al. Pyruvate kinase deficiency and malaria. N Engl J Med 2008 Apr 24; 358:1805.

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• Medline abstract (Free)

Daily JP and Sabeti P. A malaria fingerprint in the human genome? N Engl J Med 2008 Apr 24; 358:1855.

• Original article (Subscription may be required)
• Medline abstract (Free)