title: Contribution of increased ISG15, ISGylation and deregulated type I IFN signaling in Usp18 mutant mice during the course of bacterial infections.
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 (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.
authors.affiliation: 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada [2] Complex Traits Group, McGill University, Montreal, Quebec, Canada.
authors.forename: S M
authors.initials: SM
authors.lastname: Dauphinee
authors.affiliation: Department of Biology, McGill University, Montreal, Quebec, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Richer
authors.affiliation: 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada [2] Complex Traits Group, McGill University, Montreal, Quebec, Canada.
authors.forename: M M
authors.initials: MM
authors.lastname: Eva
authors.affiliation: Montreal General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: F
authors.initials: F
authors.lastname: McIntosh
authors.affiliation: Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Paquet
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Dangoor
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Burkart
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, USA.
authors.forename: D-E
authors.initials: DE
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Gruenheid
authors.affiliation: 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada [2] Complex Traits Group, McGill University, Montreal, Quebec, Canada [3] Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Gros
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Behr
authors.affiliation: 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada [2] Complex Traits Group, McGill University, Montreal, Quebec, Canada [3] Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Malo
mesh_terms: D000818:Animals; D001343:Autophagy; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D007370:Interferon Type I / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009164:Mycobacterium Infections / Q000235:genetics / Q000378:metabolism; D012480:Salmonella Infections / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism / Q000382:microbiology; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; C489550:G1p2 protein, mouse; D007370:Interferon Type I; D020381:Interleukin-17; D053583:Interleukin-1beta; D014452:Ubiquitins; C118306:Usp18 protein, mouse; D043222:Ubiquitin Thiolesterase