title: Shared and Distinct Aspects of the Sepsis Transcriptomic Response to Fecal Peritonitis and Pneumonia.
abstract: Heterogeneity in the septic response has hindered efforts to understand pathophysiology and develop targeted therapies. Source of infection, with different causative organisms and temporal changes, might influence this heterogeneity.
  
  
  
  To investigate individual and temporal variations in the transcriptomic response to sepsis due to fecal peritonitis, and to compare these with the same parameters in community-acquired pneumonia.
  
  
  
  We performed genome-wide gene expression profiling in peripheral blood leukocytes of adult patients admitted to intensive care with sepsis due to fecal peritonitis (n = 117) or community-acquired pneumonia (n = 126), and of control subjects without sepsis (n = 10).
  
  
  
  A substantial portion of the transcribed genome (18%) was differentially expressed compared with that of control subjects, independent of source of infection, with eukaryotic initiation factor 2 signaling being the most enriched canonical pathway. We identified two sepsis response signature (SRS) subgroups in fecal peritonitis associated with early mortality (P = 0.01; hazard ratio, 4.78). We defined gene sets predictive of SRS group, and serial sampling demonstrated that subgroup membership is dynamic during intensive care unit admission. We found that SRS is the major predictor of transcriptomic variation; a small number of genes (n = 263) were differentially regulated according to the source of infection, enriched for IFN signaling and antigen presentation. We define temporal changes in gene expression from disease onset involving phagosome formation as well as natural killer cell and IL-3 signaling.
  
  
  
  The majority of the sepsis transcriptomic response is independent of the source of infection and includes signatures reflecting immune response state and prognosis. A modest number of genes show evidence of specificity. Our findings highlight opportunities for patient stratification and precision medicine in sepsis.
authors.affiliation: 1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Katie L
authors.identifier: 0000-0001-8680-2933
authors.initials: KL
authors.lastname: Burnham
authors.affiliation: 1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Davenport
authors.affiliation: 1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Jayachandran
authors.initials: J
authors.lastname: Radhakrishnan
authors.affiliation: 1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Humburg
authors.affiliation: 2 Section of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, United Kingdom.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Gordon
authors.affiliation: 3 Adult Intensive Care Unit, John Radcliffe Hospital, Oxford, United Kingdom; and.
authors.forename: Paula
authors.initials: P
authors.lastname: Hutton
authors.affiliation: 4 William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University, London, United Kingdom.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Svoren-Jabalera
authors.affiliation: 3 Adult Intensive Care Unit, John Radcliffe Hospital, Oxford, United Kingdom; and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Garrard
authors.affiliation: 1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Adrian V S
authors.initials: AVS
authors.lastname: Hill
authors.affiliation: 4 William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University, London, United Kingdom.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Hinds
authors.affiliation: 1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Julian C
authors.identifier: 0000-0002-0377-5536
authors.initials: JC
authors.lastname: Knight
mesh_terms: D000368:Aged; D017714:Community-Acquired Infections / Q000097:blood / Q000235:genetics; D005243:Feces; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D010538:Peritonitis / Q000097:blood / Q000235:genetics*; D011014:Pneumonia / Q000097:blood / Q000235:genetics*; D011446:Prospective Studies; D018805:Sepsis / Q000097:blood / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*
keywords: gene expression; immune; patient stratification; septic