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Identification of genetic loci controlling bacterial clearance in experimental Salmonella enteritidis infection: an unexpected role of Nramp1 (Slc11a1) in the persistence of infection in mice

Genes & Immunity volume 3, pages 196–204 (2002)Cite this article

Abstract

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-Nramp1tm1Mcg). 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.

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Acknowledgements

We thank Dr Philippe Gros for providing Nramp1 knock out mice; Dr William Kay for providing S. enteritidis isolates; and Franck Bihl and Silvia Vidal for discussions.

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Author notes

  1. J Caron: JC is a recipient of a CIHR fellowship.

  2. J C Loredo-Osti: JCL-O is a recipient of a MITACS/Montreal General Hospital Research Institute postdoctoral fellowship.

  3. D Malo: DM is a scholar of CIHR and an International Research Scholar of the HHMI.

Authors and Affiliations

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

    J Caron, J C Loredo-Osti, E Skamene, K Morgan & D Malo

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

    J Caron, L Laroche, E Skamene, K Morgan & D Malo

  3. Department of Medicine, McGill University, Montreal, Canada

    E Skamene, K Morgan & D Malo

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  1. J Caron
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  2. J C Loredo-Osti
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  3. L Laroche
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  4. E Skamene
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  5. K Morgan
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  6. D Malo
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Corresponding author

Correspondence to D Malo.

Additional information

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).

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Caron, J., Loredo-Osti, J., Laroche, L. et al. Identification of genetic loci controlling bacterial clearance in experimental Salmonella enteritidis infection: an unexpected role of Nramp1 (Slc11a1) in the persistence of infection in mice. Genes Immun 3, 196–204 (2002). https://doi.org/10.1038/sj.gene.6363850

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