Pyruvate kinase deficiency: Correlation between enzyme activity, extent of hemolytic anemia and protection against malaria in independent mouse mutants

AcB55, AcB61 and CBA/N-Pkslc mice carry loss of function mutations in the erythrocyte specific pyruvate kinase gene (Pklr). In AcB55 and AcB61 (PklrI90N) 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 PklrG338D mutation of the CBA/N-Pkslc mutant is shown to be more deleterious than the PklrI90N 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-Pkslc mice. The CBA/N-Pkslc 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 PklrG338D mutant, CBA/N-Pkslc, than in the PklrI90N 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.