Abstract
Host genetic variants are known to confer resistance to Plasmodium blood stage infection and to control malaria severity both in humans and mice. This work describes the genetic mapping of a locus for resistance to liver stage parasite in the mouse. First, we show that decreased susceptibility to the liver stage of Plasmodium berghei in the BALB/c mouse strain is attributable to intra-hepatic factors and impacts on the initial phase of blood stage infection. We used QTL mapping techniques to identify a locus controlling this susceptibility phenotype (LOD score 4.2) on mouse chromosome 17 (belr1 locus). Furthermore, analysis of congenic mouse strains delimited the belr1 locus boundaries distally to the H2 region. Quantification of parasites in the liver of infected congenic mice strongly suggested that the belr1 locus represents a genetic factor controlling the expansion of P. berghei in the hepatic tissue. The mapping of belr1 locus raises the hypothesis that host gene variation is able to control the progression of Plasmodium liver stage infection and opens the possibility that the human genomic region orthologue to belr1 may contain genes that confer resistance to the human malaria liver stage.
Highlights
Malaria is caused by the hematoprotozoan of the genus Plasmodium and provides one of the best examples of how positive selective pressure upon host genetic variants may confer resistance to disease
Course of liver stage infection Early reports suggest that infection of BALB/c mice with
Once again the parasite burden was lower in BALB/c mice confirming that the poor expansion of P.berghei in BALB/c mice was attributable to intra-hepatic factors
Summary
Malaria is caused by the hematoprotozoan of the genus Plasmodium and provides one of the best examples of how positive selective pressure upon host genetic variants may confer resistance to disease. Genome-wide analysis using inbred mouse strains has revealed that a considerable number of chromosomal regions that enhance control of infection with different Plasmodium species (reviewed in ([3]). Genetic analysis of infection with P. chabaudi infection has identified nine loci that contribute to control of the parasitemia (char1–9) [3,4]. Analysis of recombinant mouse strains allowed the dissection of multipartite loci in char2 [5,6], char3 [7] and char4 [8] regions and to the identification of positional candidate genes for the char locus [9]. A mutation in the pyruvate kinase gene has been identified as mediating a protective mechanism to P.chabaudi infection involving increased splenic clearance of erythrocytes through hemolysis [10,11]
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