Pyruvate kinase deficiency: correlation between enzyme activity, extent of hemolytic anemia and protection against malaria in independent mouse mutants.
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.
Min-Oo
Gundula
G
Department of Biochemistry, McGill University, Montreal, Canada.
Tam
Mifong
M
Stevenson
Mary M
MM
Gros
Philippe
P
D000745:Anemia, Hemolytic, Congenital / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D000818:Animals; D004912:Erythrocytes / Q000201:enzymology / Q000276:immunology / Q000469:parasitology; D007113:Immunity, Innate / Q000235:genetics*; D008288:Malaria / Q000201:enzymology / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D016788:Plasmodium chabaudi / Q000276:immunology; D011770:Pyruvate Kinase / Q000172:deficiency*
D011770:Pyruvate Kinase