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Functional validation of the genetic architecture of Salmonella Enteritidis persistence in 129S6 mice

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Abstract

The Gram-negative bacteria, Salmonella, cause a broad spectrum of clinical diseases in humans, ranging from asymptomatic carriage to life-threatening sepsis. We have designed an experimental model to study the contribution of genetic factors to the persistence of Salmonella Enteritidis during the late phase of infection in 129S6/SvEvTac and C57BL/6J mice. C57BL/6J mice cleared the bacteria from their reticuloendothelial system within a period of 42 days, whereas the 129S6 mice still presented a high bacterial load. Using this model, we have identified ten Salmonella Enteritidis susceptibility loci (Ses1, Ses1.1, and Ses3–Ses10) associated with bacterial persistence in target organs of 129S6/SvEvTac mice using a two-locus epistasis QTL linkage mapping approach. Significant statistical interactions were detected between Ses1 on chromosome 1 and Ses5 on chromosome 7 and between Ses1 and Ses4 on chromosome X. In this study, we functionally validated the genetic architecture of Salmonella persistence in 129S6 mice using single- (129S6.B6-Ses1.2 that combines Ses1 and Ses1.1 loci, 129S6.B6-Ses4, and 129S6.B6-Ses5) and double-congenic mice (129S6.B6-Ses1.2/Ses4 and 129S6.B6-Ses1.2/Ses5). These experiments demonstrate functional interactions between Ses1.2 and Ses4 or Ses5 that improve Salmonella Enteritidis clearance, validating the critical role played by gene–gene interactions in the contribution to bacterial clearance heritability. Improved bacterial clearance in double-congenic mice could be explained by the impact of Ses4 and Ses5 in combination with Ses1.2 on TH polarization since a TH2 bias (decreased Ifng and increased Il4 mRNA levels and reduced IgG2a immunoglobulins in the serum) was observed in 129S6.B6-Ses1.2/Ses5 mice and a TH17 (high Il17 expression) bias in 129S6.B6-Ses1.2/Ses4.

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Acknowledgments

We are grateful for the excellent technical assistance of Nadia Prud’homme and Line Larivière. This work was supported by a Canadian Institutes of Health Research Grant to DM. DM is a McGill Dawson Scholar.

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Authors and Affiliations

  1. Department of Medicine, McGill University, Montreal, QC, Canada

    Marie Chevenon, Megan M. Eva, Rabia T. Khan & Danielle Malo

  2. Department of Human Genetics, McGill University, Montreal, QC, Canada

    Mayss Naccache, Megan M. Eva, Rabia T. Khan & Danielle Malo

  3. Complex Trait Group of the McGill Life Sciences Complex, McGill University, Bellini Building, 3649 Promenade Sir William Osler, Room 369, Montreal, QC, H3G 0B1, Canada

    Marie Chevenon, Megan M. Eva, Rabia T. Khan & Danielle Malo

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  1. Marie Chevenon
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Correspondence to Danielle Malo.

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Chevenon, M., Naccache, M., Eva, M.M. et al. Functional validation of the genetic architecture of Salmonella Enteritidis persistence in 129S6 mice. Mamm Genome 24, 218–227 (2013). https://doi.org/10.1007/s00335-013-9453-3

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