Open AccessThe mouse Char10 locus regulates severity of pyruvate kinase deficiency and susceptibility to malaria
Author(s) -
Aurélie Laroque,
Gundula MinOo,
Mifong Tam,
Prem Ponka,
Mary M. Stevenson,
Philippe Gros
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0177818
Subject(s) - plasmodium chabaudi , biology , pyruvate kinase deficiency , erythroblast , congenic , parasitemia , pyruvate kinase , locus (genetics) , spleen , mean corpuscular hemoglobin , microbiology and biotechnology , immunology , genetics , haematopoiesis , malaria , hematocrit , mean corpuscular volume , gene , endocrinology , plasmodium falciparum , glycolysis , metabolism , stem cell
Pyruvate kinase (PKLR) deficiency protects mice and humans against blood-stage malaria. Although mouse strain AcB62 carries a malaria-protective Pklr I90N genetic mutation, it is phenotypically susceptible to blood stage malaria induced by infection with Plasmodium chabaudi AS, suggesting a genetic modifier of the Pklr I90N protective effect. Linkage analysis in a F2 cross between AcB62 ( Pklr I90N ) and another PK deficient strain CBA/Pk ( Pklr G338D ) 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 Pklr G338D 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.