International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)


G5. Mapping and Generating Congenic Mice for Quantitative Trait Loci in Host-parasite Responses

Simon Foote, Vikki Marshall, Rachel Burt, Farah Coutrier, Lynden Roberts, Colleen Elso and James Wagglen
The Walter and Eliza Hall Institute of Medical Research, P.O. Royal Melbourne Hospital, Parkville, 3050, Australia

The host response to parasitic infection is complex. In humans there are many genetic factors implicated in response to infection by parasites. The geographic co-localisation of many genetic diseases with malaria, for example demonstrates the steps taken by the genome to lessen the clinical consequences of this disease. Presumably similar but more subtle differences exist within the immune system to fight this disease but which have not yet been identified. There are certainly differences in response to malaria and leishmania within the inbred strains of mouse. We have exploited these differences to map QTLs for response go malarial and leishmanial parasites and we have bred animals congenic for these loci.

Three loci have been mapped which modify the murine response to the murine malarial parasite, P. chabaudi . This parasite causes a severe disease resulting in the death of susceptible animals by severe anaemia. Three loci modulate the response to this parasite. Char 1and 2 control whether or not the animal survives and char 3, which maps to the H2 complex controls the rate of clearance of the parasites from the circulation. Different inbred strains of mice carry different alleles at these loci. The murine malarial parasite P. berghei causes death in mice by a cerebral syndrome, not dissimilar to that caused by the malarial parasite, P. falciparum.. There is also a difference in length of time to death by anaemia in inbred mice strains and this maps to loci responsible for outcome in the P. chabaudi model. Congenic animals have been bred for these loci and the phenotypes seen in these animals range from virtually absolute phenotypic conversion to extreme subtleties. It has been impossible to predict the phenotype of any one congenic animal ahead of time.

L. major is the causative parasite for the disease cutaneous leishmaniasis. This non-fatal disease has a rare complicated form involving the mucous membranes. Progression to muco-cutaneous disease appears to depend on the host and not the parasite. Host progression to a more serious disease is also seen in the mouse model of leishmaniasis, caused by the human parasite. We have mapped three loci responsible for the difference between sensitive and resistant strains and have generated congenic animals for all loci. Again the phenotype is subtle but present. Compound congenic animals, carrying several susceptibility loci may have a more severe phenotype.


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