RESUMO
Pyruvate kinase (PKLR) deficiency protects mice and humans against blood-stage malaria. Although mouse strain AcB62 carries a malaria-protective PklrI90N genetic mutation, it is phenotypically susceptible to blood stage malaria induced by infection with Plasmodium chabaudi AS, suggesting a genetic modifier of the PklrI90N protective effect. Linkage analysis in a F2 cross between AcB62 (PklrI90N) and another PK deficient strain CBA/Pk (PklrG338D) maps this modifier (designated Char10) to chromosome 9 (LOD = 10.8, 95% Bayesian CI = 50.7-75Mb). To study the mechanistic basis of the Char10 effect, we generated an incipient congenic line (Char10C) that harbors the Char10 chromosome 9 segment from AcB62 fixed on the genetic background of CBA/Pk. The Char10 effect is shown to be highly penetrant as the Char10C line recapitulates the AcB62 phenotype, displaying high parasitemia following P. chabaudi infection, compared to CBA/Pk. Char10C mice also display a reduction in anemia phenotypes associated with the PklrG338D mutation including decreased splenomegaly, decreased circulating reticulocytes, increased density of mature erythrocytes, increased hematocrit, as well as decreased iron overload in kidney and liver and decreased serum iron. Erythroid lineage analyses indicate that the number of total TER119+ cells as well as the numbers of the different CD71+/CD44+ erythroblast sub-populations were all found to be lower in Char10C spleen compared to CBA/Pk. Char10C mice also displayed lower number of CFU-E per spleen compared to CBA/Pk. Taken together, these results indicate that the Char10 locus modulates the severity of pyruvate kinase deficiency by regulating erythroid responses in the presence of PK-deficiency associated haemolytic anemia.
Assuntos
Anemia Hemolítica Congênita não Esferocítica/genética , Cromossomos de Mamíferos/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Malária/genética , Piruvato Quinase/deficiência , Erros Inatos do Metabolismo dos Piruvatos/genética , Anemia Hemolítica Congênita não Esferocítica/metabolismo , Anemia Hemolítica Congênita não Esferocítica/fisiopatologia , Animais , Eritrócitos/metabolismo , Eritrócitos/patologia , Eritropoese/genética , Humanos , Ferro/metabolismo , Camundongos , Piruvato Quinase/genética , Piruvato Quinase/metabolismo , Erros Inatos do Metabolismo dos Piruvatos/metabolismo , Erros Inatos do Metabolismo dos Piruvatos/fisiopatologiaRESUMO
The Plasmodium parasite successfully infects and replicates in both human and insect vectors. Population studies in humans have long detected the enormous selective pressure placed by the parasite on its human host, revealing the footprints of co-evolution. Available complete genomic sequences for the human and insect hosts, and additional sequences from multiple field isolates of Plasmodiumfalciparum have identified a wide array of protein and gene families that play a crucial role at the interface of host-parasite interaction. Selected examples of such interactions will be reviewed herein.
