Pyruvate kinase deficiency in mice protects against malaria.
The global health impact of malaria is enormous, with an estimated 300-500 million clinical cases and 1 million annual deaths. 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, beta-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 malaria. Likewise, genetic variations in erythrocyte antigens and levels of host cytokines affect type and severity of disease. 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). 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). 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.
Min-Oo
Gundula
G
Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
Fortin
Anny
A
Tam
Mi-Fong
MF
Nantel
André
A
Stevenson
Mary M
MM
Gros
Philippe
P
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D020869:Gene Expression Profiling; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D007113:Immunity, Innate / Q000235:genetics; D008288:Malaria / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D018512:Parasitemia; D016788:Plasmodium chabaudi / Q000254:growth & development / Q000502:physiology*; D011770:Pyruvate Kinase / Q000172:deficiency* / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D013163:Splenomegaly
D011770:Pyruvate Kinase