title: Survival analysis and microarray profiling identify Cd40 as a candidate for the Salmonella susceptibility locus, Ity5.
abstract: The outcome of infection with Salmonella Typhimurium in mouse models of human typhoid fever is dependent upon a coordinated complex immune response. A panel of recombinant congenic strains (RCS) derived from reciprocal backcross of A/J and C57BL/6J mice was screened for their susceptibility to Salmonella infection and two susceptibility loci, Ity4 (Immunity to Typhimurium locus 4) and Ity5, were identified. We validated Ity5 in a genetic environment free of the impact of Ity4 using a cross between A/J and 129S6. Using a time-series analysis of genome-wide transcription during infection, comparing A/J with AcB60 mice having a C57BL/6J-derived Ity5 interval, we have identified the differential expression of the positional candidate gene Cd40, Cd40-associated signaling pathways, and the differential expression of numerous genes expressed in neutrophils. CD40 is known to coordinate T cell-dependent B-cell responses and myeloid cell activation. In fact, CD40 signaling is altered in A/J mice as seen by impaired IgM upregulation during infection, decreased Ig class switching, neutropenia, reduced granulocyte recruitment in response to infection and inflammation, and decreased ERK1/2 activity. These results suggest that altered CD40 signaling and granulocyte recruitment in response to infection are responsible for the Ity5-associated Salmonella susceptibility of A/J mice.
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Quebec Canada.|Complex Traits Group of the McGill Life Sciences Complex, McGill University, Montréal, Quebec Canada.
authors.forename: S C
authors.identifier: http://orcid.org/0000-0001-6819-7071
authors.initials: SC
authors.lastname: Beatty
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Quebec Canada.|Complex Traits Group of the McGill Life Sciences Complex, McGill University, Montréal, Quebec Canada.
authors.forename: K E
authors.initials: KE
authors.lastname: Yuki
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Quebec Canada.|Complex Traits Group of the McGill Life Sciences Complex, McGill University, Montréal, Quebec Canada.
authors.forename: M M
authors.initials: MM
authors.lastname: Eva
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Quebec Canada.|Complex Traits Group of the McGill Life Sciences Complex, McGill University, Montréal, Quebec Canada.
authors.forename: S
authors.initials: S
authors.lastname: Dauphinee
authors.affiliation: Complex Traits Group of the McGill Life Sciences Complex, McGill University, Montréal, Quebec Canada.
authors.forename: L
authors.initials: L
authors.lastname: Larivière
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Quebec Canada.|Complex Traits Group of the McGill Life Sciences Complex, McGill University, Montréal, Quebec Canada.|Department of Medicine, McGill University, Montréal, Quebec Canada.
authors.forename: S M
authors.initials: SM
authors.lastname: Vidal
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Quebec Canada.|Complex Traits Group of the McGill Life Sciences Complex, McGill University, Montréal, Quebec Canada.|Department of Medicine, McGill University, Montréal, Quebec Canada.
authors.forename: D
authors.initials: D
authors.lastname: Malo
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000276:immunology*; D027682:Cation Transport Proteins / Q000235:genetics* / Q000276:immunology; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D007136:Immunoglobulins / Q000276:immunology; D020935:MAP Kinase Signaling System; D051379:Mice / Q000145:classification / Q000235:genetics / Q000276:immunology; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation; D012481:Salmonella Infections, Animal / Q000276:immunology*; D000099173:Natural Resistance-associated Macrophage Protein 1
chemical_list: D019013:CD40 Antigens; D027682:Cation Transport Proteins; D007136:Immunoglobulins; D000099173:Natural Resistance-associated Macrophage Protein 1