title: Complex genetics architecture contributes to Salmonella resistance in AcB60 mice.
abstract: Human infection with Salmonella is of global public health concern. In low- and middle-income countries, Salmonella infection is a major source of disease in terms of both mortality and morbidity, while in high-income nations, the pathogen is an ongoing threat to food security. The outcome of infection with Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) in mouse models is dependent upon a coordinated and complex immune response. A panel of recombinant congenic strains (RCS) derived from the reciprocal double backcross of A/J and C57BL/6J mice has been screened for their susceptibility to Salmonella infection, and the RCS AcB60 was identified to be the most resistant strain to Salmonella infection, more resistant than the parental strain A/J. These mice are known to carry resistant alleles at three well-defined Salmonella susceptibility loci, Slc11a1Ity(solute carrier family 11 member 1; Immunity to Typhimurium locus), PklrIty4(pyruvate kinase liver and red blood cell; Ity4 locus), and Ity5. In the current study, we used interval mapping to validate a locus on Chr 15, named Ity8, linked to Salmonella resistance in AcB60 mice. Global gene expression analysis during infection identified AcB60-specific expression of genes involved in Ccr7 signaling, including downstream effector Mapk11 (mitogen-activated protein kinase 11), located within the Ity8 interval, and representing a potential positional candidate gene. An additional region on Chr 18 of C57BL/6J descent was shown to be associated with increase resistance in AcB60. These observations provide an opportunity to achieve new insight into the complex genetics of resistance to Salmonella infection in the context of mouse models of human infection with Salmonella Typhimurium.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, H3G 0B1, Canada.|McGill University Research Centre on Complex Traits, McGill University, McGill Life Sciences Complex, Bellini Building, 3649 Promenade Sir William Osler, Room 369, Montreal, QC, H3G 0B1, Canada.
authors.forename: Sean
authors.initials: S
authors.lastname: Beatty
authors.affiliation: McGill University Research Centre on Complex Traits, McGill University, McGill Life Sciences Complex, Bellini Building, 3649 Promenade Sir William Osler, Room 369, Montreal, QC, H3G 0B1, Canada.
authors.forename: Leïla
authors.initials: L
authors.lastname: Rached-D'Astous
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, H3G 0B1, Canada. danielle.malo@mcgill.ca.|Department of Medicine, McGill University, Montreal, QC, H3G 0B1, Canada. danielle.malo@mcgill.ca.|McGill University Research Centre on Complex Traits, McGill University, McGill Life Sciences Complex, Bellini Building, 3649 Promenade Sir William Osler, Room 369, Montreal, QC, H3G 0B1, Canada. danielle.malo@mcgill.ca.
authors.forename: Danielle
authors.identifier: 0000-0003-3980-6610
authors.initials: D
authors.lastname: Malo
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D048290:Mitogen-Activated Protein Kinase 11 / Q000235:genetics*; D054400:Receptors, CCR7 / Q000235:genetics*; D012480:Salmonella Infections / Q000235:genetics* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000472:pathogenicity; D000099173:Natural Resistance-associated Macrophage Protein 1
chemical_list: D027682:Cation Transport Proteins; D048290:Mitogen-Activated Protein Kinase 11; D054400:Receptors, CCR7; D000099173:Natural Resistance-associated Macrophage Protein 1; C515371:Ccr7 protein, mouse