Genetic control of host:pathogen interactions in mice
The onset, progression and outcome of infections are determined by performance of host defense mechanisms and expression of pathogen virulence determinants. Genetic analysis in mouse can identify host genes that play critical roles at the interface of host:pathogen interaction. Genetic effects detected as variations in susceptibility in inbred, recombinant and mutant strains of mice can be mapped as simple traits or quantitative trait loci followed by identification by positional cloning. Our laboratory has been successfull in identifying and charcaterizing a number of single gene effects that affect resistance to infection with several bacterial and fungal pathogens. Recently, we have used a mouse model of infection with Plasmodium chabaudi AS to identify genes that regulate blood stage replication of the malarial parasite. Independent mutations in erythrocyte pyruvate kinase (Char4) of AcB55/61 (PklrI90N) and CBA-Pk-1slc (PklrG338D) protect against erythrocyte replication and lethality following P. chabaudi AS infection. We have also characterized a novel locus, Char9 (Chr. 10), that further regulates P. chabaudi AS replication in [AcB55xA]F2 mice and which protective effect is additive to that of mutant Pk alleles. We have localized a QTL on proximal Chr. 9 (Char10) that confers susceptibility to malaria in AcB62 mice despite presence of a protective mutant PklrI90N allele Pklr. Finally, we show that the transcriptional regulator Icsbp/IRF8 that is mutated in BXH2 is essential for curative immune response following P. chabaudi AS infection.