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Contribution of increased ISG15, ISGylation and deregulated type I IFN signaling in Usp18 mutant mice during the course of bacterial infections

Genes & Immunity volume 15, pages 282–292 (2014)Cite this article

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Abstract

Host genetics has a key role in susceptibility to Salmonella Typhimurium infection. We previously used N-ethyl-N-nitrosourea (ENU) mutagenesis to identify a loss-of-function mutation within the gene ubiquitin-specific peptidase 18 (Usp18Ity9), which confers increased susceptibility to Salmonella Typhimurium. USP18 functions to regulate type I interferon (IFN) signaling and as a protease to remove ISG15 from substrate proteins. Usp18Ity9 mice are susceptible to infection with Salmonella Typhimurium and have increased expression and function of ISG15, but Usp18Ity9 mice lacking Isg15 do not show improved survival with Salmonella challenge. Type I IFN signaling is increased in Usp18Ity9 mice and inhibition of type I IFN signaling is associated with improved survival in mutant mice. Hyperactivation of type I IFN signaling leads to increased IL-10, deregulated expression of autophagy markers and elevated interleukin (IL)-1β and IL-17. Furthermore, Usp18Ity9 mice are more susceptible to infection with Mycobacterium tuberculosis, have increased bacterial load in the lung and spleen, elevated inflammatory cytokines and more severe lung pathology. These findings demonstrate that regulation of type I IFN signaling is the predominant mechanism affecting the susceptibility of Usp18Ity9 mice to Salmonella infection and that hyperactivation of signaling leads to increased IL-10, deregulation of autophagic markers and increased proinflammatory cytokine production.

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Acknowledgements

We are grateful for the technical assistance of Nadia Prud’homme, Patricia D’arcy, Genevieve Perrault, Lei Zhu, Kyoko Yuki and Line Larivière. SMD is the recipient of a fellowship award from the Fonds de la recherche en santé du Québec. This work was supported by a Canadian Institutes of Health Research Team Grant (CTP-87520) to DM and PG, as well as an United States NIH HL091549 to D-EZ. PG is a James McGill Professor and DM is a McGill Dawson Scholar.

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Authors and Affiliations

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

    S M Dauphinee, M M Eva, P Gros & D Malo

  2. Complex Traits Group, McGill University, Montreal, Quebec, Canada

    S M Dauphinee, M M Eva, P Gros & D Malo

  3. Department of Biology, McGill University, Montreal, Quebec, Canada

    E Richer

  4. Montreal General Hospital, McGill University, Montreal, Quebec, Canada

    F McIntosh

  5. Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec, Canada

    M Paquet

  6. Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

    D Dangoor & C Burkart

  7. Department of Pathology, University of California San Diego, La Jolla, CA, USA

    D-E Zhang

  8. Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada

    S Gruenheid

  9. Department of Biochemistry, McGill University, Montreal, Quebec, Canada

    P Gros

  10. Department of Medicine, McGill University, Montreal, Quebec, Canada

    M Behr & D Malo

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Dauphinee, S., Richer, E., Eva, M. et al. Contribution of increased ISG15, ISGylation and deregulated type I IFN signaling in Usp18 mutant mice during the course of bacterial infections. Genes Immun 15, 282–292 (2014). https://doi.org/10.1038/gene.2014.17

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