¹Department of Human Genetics, McGill University, Montreal, Canada

²Center for the Study of Host Resistance, McGill University, Montreal, Canada

³Department of Medicine, McGill University, Montreal, Canada

Correspondence to: Dr D Malo, McGill University Health Center, Montreal General Hospital Research Institute, 1650 Cedar Avenue, Rm. L11-144, Montreal, Quebec, Canada, H3G 1A4. E-mail: danielle.malo@mcgill.ca

^aJC is a recipient of a CIHR fellowship.

^bJCL-O is a recipient of a MITACS/Montreal General Hospital Research Institute postdoctoral fellowship.

^cDM is a scholar of CIHR and an International Research Scholar of the HHMI.

This work was supported by grants from the Canadian Networks of Centers of Excellence Program - the Canadian Genetic Diseases Network (CGDN, KM), the Mathematics of Information Technology and Complex Systems Network (MITACS, KM) and the Canadian Bacterial Diseases Network (CBDN, DM); the Canadian Institutes of Health Research (CIHR) and the Howard Hughes Medical Institute (Infectious Diseases and Parasitology Program).

The Gram-negative bacteria, Salmonella, cause a broad spectrum of clinical diseases in both animals and humans ranging from asymptomatic carriage to life-threatening sepsis. We have developed a model to study the contribution of genetic factors to the susceptibility of 129sv and C57BL/6J inbred mice to Salmonella enteritidis during the late phase of infection. C57BL/6J mice were able to eliminate completely sublethal inoculums of S. enteritidis from their reticuloendothelial system, whereas 129sv mice could not even after 60 days post inoculation. A genome scan performed on 302 (C57BL/6J ´ 129sv) F2 progeny identified three dominant loci (designated Ses1 to Ses3) that are associated with disease susceptibility in 129sv mice. Two highly significant linkages were identified on chromosomes 1 (Ses1) and 7 (Ses2) with respective LOD scores of 9.9 (P = 1.4 ´ 10^-11) at D1Mcg5 and 4.0 (P = 1.9 ´ 10^-5) at D7Mit62. One highly suggestive QTL was located on chromosomes15 (Ses3) with a LOD score 3.4 (P = 1.2 ´ 10^-4). The estimated effects of Ses1, Ses2 and Ses3 on the bacterial clearance were greater in females. Using a model of three loci, with interaction between Ses1 and Ses2 and sex as a covariate, the three QTLs explained 32% of the phenotypic variance. The candidacy of Nramp1 as the gene for Ses1 was evaluated using mice carrying a null allele at Nramp1 (129sv-Nramp1^tm1Mcg). These mice have a significantly lower spleen bacterial load compared to the wild-type 129sv mice, strongly suggesting the involvement of Nramp1 in controlling S. enteritidis clearance during the late phase of infection.

Genes and Immunity (2002) 3, 196-204. doi:10.1038/sj.gene.6363850

Salmonella; mouse model; complex trait; QTL; Nramp1