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Survival analysis and microarray profiling identify Cd40 as a candidate for the Salmonella susceptibility locus, Ity5

Genes & Immunity volume 17, pages 19–29 (2016)Cite this article

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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.

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Acknowledgements

We are very grateful for the technical support of Nadia Prud’homme, Catherine Paré, Stuart Foster, Leïla Rached-D’Astous and for the assistance with data analysis provided by Robert Nadon. This work was supported by Canadian Institutes of Health Research (CIHR) Grants to DM (MOP-15461) and to SMV (MOP-89821).

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Authors and Affiliations

  1. Department of Human Genetics, McGill University, Montréal, Quebec, Canada

    S C Beatty, K E Yuki, M M Eva, S Dauphinee, S M Vidal & D Malo

  2. Complex Traits Group of the McGill Life Sciences Complex, McGill University, Montréal, Quebec, Canada

    S C Beatty, K E Yuki, M M Eva, S Dauphinee, L Larivière, S M Vidal & D Malo

  3. Department of Medicine, McGill University, Montréal, Quebec, Canada

    S M Vidal & D Malo

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  1. S C Beatty
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Correspondence to D Malo.

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Beatty, S., Yuki, K., Eva, M. et al. Survival analysis and microarray profiling identify Cd40 as a candidate for the Salmonella susceptibility locus, Ity5. Genes Immun 17, 19–29 (2016). https://doi.org/10.1038/gene.2015.41

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