N-ethyl-N-nitrosourea-induced mutation in ubiquitin-specific peptidase 18 causes hyperactivation of IFN-αß signaling and suppresses STAT4-induced IFN-γ production, resulting in increased susceptibility to Salmonella typhimurium.
To deepen our knowledge of the natural host response to pathogens, our team undertook an in vivo screen of mutagenized 129S1 mice with Salmonella Typhimurium. One mutation affecting Salmonella susceptibility was mapped to a region of 1.3 Mb on chromosome 6 that contains 15 protein-coding genes. A missense mutation was identified in the Usp18 (ubiquitin-specific peptidase 18) gene. This mutation results in an increased inflammatory response (IL-6, type 1 IFN) to Salmonella and LPS challenge while paradoxically reducing IFN-gamma production during bacterial infection. Increased STAT1 phosphorylation correlated with impaired STAT4 phosphorylation, resulting in overwhelming IL-6 secretion but reduced IFN-gamma production during infection. The reduced IFN-gamma levels, along with the increased inflammation, rationalize the S. Typhimurium susceptibility in terms of increased bacterial load in target organs and cytokine-induced septic shock and death.
Richer
Etienne
E
Department of Human Genetics, McGill University, Montréal, Québec, Canada.
Prendergast
Caitlin
C
Zhang
Dong-Er
DE
Qureshi
Salman T
ST
Vidal
Silvia M
SM
Malo
Danielle
D
D000818:Animals; D010450:Endopeptidases / Q000172:deficiency / Q000235:genetics*; D005038:Ethylnitrosourea / Q000633:toxicity*; D005260:Female; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D016898:Interferon-alpha / Q000502:physiology*; D016899:Interferon-beta / Q000502:physiology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009153:Mutagens / Q000633:toxicity; D020125:Mutation, Missense / Q000187:drug effects; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D050797:STAT4 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D012481:Salmonella Infections, Animal / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D025801:Ubiquitin / Q000276:immunology; D043222:Ubiquitin Thiolesterase
D016898:Interferon-alpha; D009153:Mutagens; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D025801:Ubiquitin; D016899:Interferon-beta; D007371:Interferon-gamma; D010450:Endopeptidases; C118306:Usp18 protein, mouse; D043222:Ubiquitin Thiolesterase; D005038:Ethylnitrosourea