Abstract
The host response to infection in humans is multifactorial and involves the complex interaction between two genomes (the host and the pathogen) and the environment. Using an experimental mouse model of chronic infection, we have previously identified the individual effect of three significant and one suggestive quantitative trait loci (QTLs) (Ses1, Ses2, Ses3 and Ses1.1) on Salmonella Enteritidis persistence in target organs of 129S6/SvEvTac mice. Congenic strain construction was performed by transferring each of these QTLs from C57BL/6J onto the 129S6/SvEvTac background, and phenotypic analysis confirmed that Ses1 and Ses1.1 contribute to bacterial clearance. Additional QTLs regulating Salmonella carriage in 129S6/SvEvTac mice were identified using a two-locus epistasis QTL linkage mapping approach conducted separately in females and males. The epistatic model for females included the individual effect of Ses3 and two significant interactions (Ses1–D7Mit267 and Ses1–DXMit48) accounting for 47% of the total phenotypic variance. The model for males included the individual effect of Ses1.1, three interactions (Ses1–D9Mit218, D2Mit197–D4Mit2 and D3Mit256–D13Mit36) and explained 47% of the phenotypic variance. Our results suggest that the oligogenic nature of Salmonella persistence and epistasis are important constituents of the genetic architecture of the host response to chronic Salmonella infection.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 digital issues and online access to articles
$119.00 per year
only $19.83 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
CDC. Center for Disease Control and Prevention Report. Division of bacterial and mycotic diseases. Disease information, www.cdc.gov, Atlanta, Giorgia, December 2003.
Roy MF, Malo D . Genetic regulation of host responses to Salmonella infection in mice. Genes Immun 2002; 3: 381–393.
O'Brien AD, Scher I, Formal SB . Effect of silica on the innate resistance of inbred mice to Salmonella typhimurium infection. Infect Immun 1979; 25: 513–520.
Nauciel C, Vilde F, Ronco E . Host response to infection with a temperature-sensitive mutant of Salmonella typhimurium in a susceptible and a resistant strain of mice. Infect Immun 1985; 49: 523–527.
Barthel M, Hapfelmeier S, Quintanilla-Martinez L et al. Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infect Immun 2003; 71: 2839–2858.
Young D, Hussell T, Dougan G . Chronic bacterial infections: living with unwanted guests. Nat Immunol 2002; 3: 1026–1032.
Monack DM, Bouley DM, Falkow S . Salmonella typhimurium persists within macrophage. J Exp Med 2004; 199: 231–241.
Caron J, Loredo-Osti JC, Laroche L, Skamene E, Morgan K, Malo D . 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 2002; 3: 196–204.
Kim JH, Sen S, Avery CS et al. Genetic analysis of a new mouse model for non-insulin-dependent diabetes. Genomics 2001; 74: 273–286.
Xu J, Langefeld CD, Zheng SL et al. Interaction effect of PTEN and CDKN1B chromosomal regions on prostate cancer linkage. Hum Genet 2004; 115: 255–262.
Buer J, Balling R . Mice, microbes and models of infection. Nat Rev Genet 2003; 4: 195–205.
Casanova JL, Abel L . The human model: a genetic dissection of immunity to infection in natural conditions. Nat Rev Immunol 2004; 4: 55–66.
Sukupolvi S, Edelstein A, Rhen M, Normark SJ, Pfeifer JD . Development of a murine model of chronic Salmonella infection. Infect Immun 1997; 65: 838–842.
Malo D, Vogan K, Vidal S et al. Haplotype mapping and sequence analysis of the mouse Nramp gene predict susceptibility to infection with intracellular parasites. Genomics 1994; 23: 51–61.
Vidal S, Tremblay ML, Govoni G et al. The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene. J Exp Med 1995; 182: 655–666.
Carlborg O, Haley CS . Epistasis: too often neglected in complex trait studies? Nat Rev Genet 2004; 5: 618–625.
Kao CH, Zeng ZB, Teasdale RD . Multiple interval mapping for quantitative trait loci. Genetics 1999; 152: 1203–1216.
Pociot F, Karlsen AE, Pedersen CB, Aalund M, Nerup J . Novel analytical methods applied to type 1 diabetes genome-scan data. Am J Hum Genet 2004; 74: 647–660.
Naumova AK, Leppert M, Barker DF, Morgan K, Sapienza C . Parental origin-dependent, male offspring-specific transmission-ratio distortion at loci on the human X chromosome. Am J Hum Genet 1998; 62: 1493–1499.
Naumova A, Sapienza C . The genetics of retinoblastoma, revisited. Am J Hum Genet 1994; 54: 264–273.
Naumova AK, Greenwood CM, Morgan K . Imprinting and deviation from Mendelian transmission ratios. Genome 2001; 44: 311–320.
Croteau S, Andrade MF, Huang F, Greenwood CM, Morgan K, Naumova AK . Inheritance patterns of maternal alleles in imprinted regions of the mouse genome at different stages of development. Mamm Genome 2002; 13: 24–29.
Cattanach BM, Beechey CV, Peters J . Interactions between imprinting effects in the mouse. Genetics 2004; 168: 397–413.
Vidal SM, Pinner E, Lepage P, Gauthier S, Gros P . Natural resistance to intracellular infections: Nramp1 encodes a membrane phosphoglycoprotein absent in macrophages from susceptible (Nramp1 D169) mouse strains. J Immunol 1996; 157: 3559–3568.
Gruenheid S, Finlay BB . Microbial pathogenesis and cytoskeletal function. Nature 2003; 422: 775–781.
Forbes JR, Gros P . Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood 2003; 102: 1884–1892.
Gruenheid S, Pinner E, Desjardins M, Gros P . Natural resistance to infection with intracellular pathogens: the Nramp1 protein is recruited to the membrane of the phagosome. J Exp Med 1997; 185: 717–730.
Cuellar-Mata P, Jabado N, Liu J et al. Nramp1 modifies the fusion of Salmonella typhimurium-containing vacuoles with cellular endomembranes in macrophages. J Biol Chem 2002; 277: 2258–2265.
Jabado N, Cuellar-Mata P, Grinstein S, Gros P . Iron chelators modulate the fusogenic properties of Salmonella-containing phagosomes. Proc Natl Acad Sci USA 2003; 100: 6127–6132.
Singh PK, Parsek MR, Greenberg EP, Welsh MJ . A component of innate immunity prevents bacterial biofilm development. Nature 2002; 417: 552–555.
Nicolas G, Bennoun M, Devaux I et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 2001; 98: 8780–8785.
Nicolas G, Viatte L, Bennoun M, Beaumont C, Kahn A, Vaulont S . Hepcidin, a new iron regulatory peptide. Blood Cells Mol Dis 2002; 29: 327–335.
Pigeon C, Ilyin G, Courselaud B et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001; 276: 7811–7819.
Shike H, Lauth X, Westerman ME et al. Bass hepcidin is a novel antimicrobial peptide induced by bacterial challenge. Eur J Biochem 2002; 269: 2232–2237.
Ashrafian H . Hepcidin: the missing link between hemochromatosis and infections. Infect Immun 2003; 71: 6693–6700.
Sebastiani G, Olien L, Gauthier S et al. Mapping of genetic modulators of natural resistance to infection with Salmonella typhimurium in wild-derived mice. Genomics 1998; 47: 180–186.
Ihaka RGR . R: a language for data analysis and graphics. J Comput Graph Stat 1996; 5: 299–314.
Broman KW, Wu H, Sen S, Churchill GA . R/qtl: QTL mapping in experimental crosses. Bioinformatics 2003; 19: 889–890.
Miller A . Subset Selection in Regression. Chapman and Hall: New York, 2002.
Scharz G . Estimating the dimension of a model. Ann Stat 1978; 6: 461–464.
Davison ACHD . Bootstrap Methods and Their Application. 4th edn. Cambridge University Press: Cambridge, 1997.
Acknowledgements
We thank Dr William Kay for providing S Enteritidis isolates and Rosalie Wilkinson and Line Larivière for their technical expertise. We also thank Dr Thomas Hudson, Dr Andrei Verner and Geneviève Geneau at the McGill University and Génome Québec Innovation Centre for their technical help and the use of their facility and equipment to perform the fluorescent genotyping work. We thank Dr Silvia Vidal for helpful discussions and critical review of the manuscript. This work was supported by grants from the Canadian Institutes of Health Research (CIHR), the Howard Hughes Medical Institute (HHMI, Infectious Diseases and Parasitology Program), the Canadian Genetic Diseases Network and the Mathematics of Information Technology and Complex System Network (Networks of Centres of Excellence Program). JC is the recipient of a CIHR fellowship. JCL-O is a CIHR Strategic Training Fellow in Infectious Diseases and Autoimmunity. DM is a scholar of CIHR and an International Research Scholar of the HHMI.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Caron, J., Loredo-Osti, J., Morgan, K. et al. Mapping of interactions and mouse congenic strains identified novel epistatic QTLs controlling the persistence of Salmonella Enteritidis in mice. Genes Immun 6, 500–508 (2005). https://doi.org/10.1038/sj.gene.6364234
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gene.6364234
Keywords
This article is cited by
-
Functional validation of the genetic architecture of Salmonella Enteritidis persistence in 129S6 mice
Mammalian Genome (2013)
-
A locus on chromosome 9 is associated with differential response of 129S1/SvImJ and FVB/NJ strains of mice to systemic LPS
Mammalian Genome (2011)
-
Complexity in the host response to Salmonella Typhimurium infection in AcB and BcA recombinant congenic strains
Genes & Immunity (2006)
-
Complex genetic control of susceptibility to Mycobacterium bovis (Bacille Calmette-Guérin) infection in wild-derived Mus spretus mice
Genes & Immunity (2006)