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

Genes Immun. Jul-Aug 2014;15(5):282-92. doi: 10.1038/gene.2014.17. Epub 2014 May 8.


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 (Usp18(Ity9)), 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. Usp18(Ity9) mice are susceptible to infection with Salmonella Typhimurium and have increased expression and function of ISG15, but Usp18(Ity9) mice lacking Isg15 do not show improved survival with Salmonella challenge. Type I IFN signaling is increased in Usp18(Ity9) 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, Usp18(Ity9) 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 Usp18(Ity9) mice to Salmonella infection and that hyperactivation of signaling leads to increased IL-10, deregulation of autophagic markers and increased proinflammatory cytokine production.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Interferon Type I / metabolism*
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Lung / metabolism
  • Lung / microbiology
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mutation*
  • Mycobacterium Infections / genetics
  • Mycobacterium Infections / metabolism
  • Salmonella Infections / genetics*
  • Salmonella Infections / metabolism
  • Signal Transduction*
  • Spleen / metabolism
  • Spleen / microbiology
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitins / genetics
  • Ubiquitins / metabolism


  • Cytokines
  • G1p2 protein, mouse
  • Interferon Type I
  • Interleukin-17
  • Interleukin-1beta
  • Ubiquitins
  • Usp18 protein, mouse
  • Ubiquitin Thiolesterase