title: Late multiple organ surge in interferon-regulated target genes characterizes staphylococcal enterotoxin B lethality.
abstract: BACKGROUND
  Bacterial superantigens are virulence factors that cause toxic shock syndrome. Here, the genome-wide, temporal response of mice to lethal intranasal staphylococcal enterotoxin B (SEB) challenge was investigated in six tissues.
  
  
  RESULTS
  The earliest responses and largest number of affected genes occurred in peripheral blood mononuclear cells (PBMC), spleen, and lung tissues with the highest content of both T-cells and monocyte/macrophages, the direct cellular targets of SEB. In contrast, the response of liver, kidney, and heart was delayed and involved fewer genes, but revealed a dominant genetic program that was seen in all 6 tissues. Many of the 85 uniquely annotated transcripts participating in this shared genomic response have not been previously linked to SEB. Nine of the 85 genes were subsequently confirmed by RT-PCR in every tissue/organ at 24 h. These 85 transcripts, up-regulated in all tissues, annotated to the interferon (IFN)/antiviral-response and included genes belonging to the DNA/RNA sensing system, DNA damage repair, the immunoproteasome, and the ER/metabolic stress-response and apoptosis pathways. Overall, this shared program was identified as a type I and II interferon (IFN)-response and the promoters of these genes were highly enriched for IFN regulatory matrices. Several genes whose secreted products induce the IFN pathway were up-regulated at early time points in PBMCs, spleen, and/or lung. Furthermore, IFN regulatory factors including Irf1, Irf7 and Irf8, and Zbp1, a DNA sensor/transcription factor that can directly elicit an IFN innate immune response, participated in this host-wide SEB signature.
  
  
  CONCLUSIONS
  Global gene-expression changes across multiple organs implicated a host-wide IFN-response in SEB-induced death. Therapies aimed at IFN-associated innate immunity may improve outcome in toxic shock syndromes.
authors.affiliation: Functional Genomics and Proteomics Facility, Critical Care Medicine Department, Clinical Research Center, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Gabriela A
authors.initials: GA
authors.lastname: Ferreyra
authors.affiliation: Functional Genomics and Proteomics Facility, Critical Care Medicine Department, Clinical Research Center, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Elinoff
authors.affiliation: Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Cumhur Y
authors.initials: CY
authors.lastname: Demirkale
authors.affiliation: Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Starost
authors.affiliation: Integrated Toxicology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Buckley
authors.affiliation: Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Munson
authors.affiliation: Integrated Toxicology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Teresa
authors.initials: T
authors.lastname: Krakauer
authors.affiliation: Functional Genomics and Proteomics Facility, Critical Care Medicine Department, Clinical Research Center, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D004768:Enterotoxins; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D007113:Immunity, Innate / Q000235:genetics*; D007274:Injections, Intraperitoneal; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D011401:Promoter Regions, Genetic; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis; D059467:Transcriptome / Q000276:immunology*
chemical_list: D004768:Enterotoxins; D050835:Interferon Regulatory Factors; C031818:enterotoxin B, staphylococcal