title: Altered IFN-γ-mediated immunity and transcriptional expression patterns in N-Ethyl-N-nitrosourea-induced STAT4 mutants confer susceptibility to acute typhoid-like disease.
abstract: Salmonella enterica is a ubiquitous Gram-negative intracellular bacterium that continues to pose a global challenge to human health. The etiology of Salmonella pathogenesis is complex and controlled by pathogen, environmental, and host genetic factors. In fact, patients immunodeficient in genes in the IL-12, IL-23/IFN-γ pathway are predisposed to invasive nontyphoidal Salmonella infection. Using a forward genomics approach by N-ethyl-N-nitrosourea (ENU) germline mutagenesis in mice, we identified the Ity14 (Immunity to Typhimurium locus 14) pedigree exhibiting increased susceptibility following in vivo Salmonella challenge. A DNA-binding domain mutation (p.G418_E445) in Stat4 (Signal Transducer and Activator of Transcription Factor 4) was the causative mutation. STAT4 signals downstream of IL-12 to mediate transcriptional regulation of inflammatory immune responses. In mutant Ity14 mice, the increased splenic and hepatic bacterial load resulted from an intrinsic defect in innate cell function, IFN-γ-mediated immunity, and disorganized granuloma formation. We further show that NK and NKT cells play an important role in mediating control of Salmonella in Stat4(Ity14/Ity14) mice. Stat4(Ity14/Ity14) mice had increased expression of genes involved in cell-cell interactions and communication, as well as increased CD11b expression on a subset of splenic myeloid dendritic cells, resulting in compromised recruitment of inflammatory cells to the spleen during Salmonella infection. Stat4(Ity14/Ity14) presented upregulated compensatory mechanisms, although inefficient and ultimately Stat4(Ity14/Ity14) mice develop fatal bacteremia. The following study further elucidates the pathophysiological impact of STAT4 during Salmonella infection.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3G 0B1, Canada;
authors.forename: Megan M
authors.initials: MM
authors.lastname: Eva
authors.forename: Kyoko E
authors.initials: KE
authors.lastname: Yuki
authors.forename: Shauna M
authors.initials: SM
authors.lastname: Dauphinee
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Schwartzentruber
authors.forename: Michal
authors.initials: M
authors.lastname: Pyzik
authors.forename: Marilène
authors.initials: M
authors.lastname: Paquet
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Vidal
authors.forename: Danielle
authors.initials: D
authors.lastname: Malo
mesh_terms: D000818:Animals; D058491:Bacterial Load; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics; D016000:Cluster Analysis; D004252:DNA Mutational Analysis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D009154:Mutation / Q000187:drug effects; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D009607:Nitrosourea Compounds / Q000633:toxicity; D010375:Pedigree; D050797:STAT4 Transcription Factor / Q000235:genetics*; D012481:Salmonella Infections, Animal / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D012486:Salmonella typhimurium / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D014158:Transcription, Genetic; D059467:Transcriptome; D000099173:Natural Resistance-associated Macrophage Protein 1
chemical_list: D039481:CD11b Antigen; D027682:Cation Transport Proteins; D007371:Interferon-gamma; D009607:Nitrosourea Compounds; D050797:STAT4 Transcription Factor; D000099173:Natural Resistance-associated Macrophage Protein 1