title: Genome-wide sequencing of cellular microRNAs identifies a combinatorial expression signature diagnostic of sepsis.
abstract: BACKGROUND
  Sepsis is a common cause of death in the intensive care unit with mortality up to 70% when accompanied by multiple organ dysfunction. Rapid diagnosis and the institution of appropriate antibiotic therapy and pressor support are therefore critical for survival. MicroRNAs are small non-coding RNAs that play an important role in the regulation of numerous cellular processes, including inflammation and immunity.
  
  
  OBJECTIVE
  We hypothesized changes in expression of microRNAs during sepsis may be of diagnostic value in the intensive care unit (ICU).
  
  
  METHODS
  Massively parallel sequencing of microRNAs was utilised for screening microRNA candidates. Putative microRNAs were validated using quantitative real-time PCR (qRT-PCR). This study includes data from both a training cohort (UK) and an independent validation cohort (Sweden). A linear discriminant statistical model was employed to construct a diagnostic microRNA signature.
  
  
  RESULTS
  A panel of known and novel microRNAs were detectable in the blood of patients with sepsis. After qRT-PCR validation, microRNA miR-150 and miR-4772-5p-iso were able to discriminate between patients who have systemic inflammatory response syndrome and patients with sepsis. This finding was also validated in independent cohort with an average diagnostic accuracy of 86%. Fractionating the cellular components of blood reveals miR-4772-5p-iso is expressed differentially in monocytes. Functional experiments using primary human monocytes demonstrate that it expressed in response to TLR ligation.
  
  
  CONCLUSIONS
  Taken together, these data provide a novel microRNA signature of sepsis that should allow rapid point-of-care diagnostic assessment of patients on ICU and also provide greater insight into the pathobiology of this severe disease.
authors.affiliation: Department of Experimental Immunobiology, King's College London, London, United Kingdom ; NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, United Kingdom.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Ma
authors.forename: David
authors.initials: D
authors.lastname: Vilanova
authors.forename: Kerem
authors.initials: K
authors.lastname: Atalar
authors.forename: Olivier
authors.initials: O
authors.lastname: Delfour
authors.forename: Jonathan
authors.initials: J
authors.lastname: Edgeworth
authors.forename: Marlies
authors.initials: M
authors.lastname: Ostermann
authors.forename: Maria
authors.initials: M
authors.lastname: Hernandez-Fuentes
authors.forename: Sandrine
authors.initials: S
authors.lastname: Razafimahatratra
authors.forename: Bernard
authors.initials: B
authors.lastname: Michot
authors.forename: David H
authors.initials: DH
authors.lastname: Persing
authors.forename: Ingrid
authors.initials: I
authors.lastname: Ziegler
authors.forename: Bianca
authors.initials: B
authors.lastname: Törös
authors.forename: Paula
authors.initials: P
authors.lastname: Mölling
authors.forename: Per
authors.initials: P
authors.lastname: Olcén
authors.forename: Richard
authors.initials: R
authors.lastname: Beale
authors.forename: Graham M
authors.initials: GM
authors.lastname: Lord
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007362:Intensive Care Units; D016014:Linear Models; D008297:Male; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D018805:Sepsis / Q000097:blood* / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D059467:Transcriptome
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; C533097:MIR150, human