title: Identification of a human neonatal immune-metabolic network associated with bacterial infection.
abstract: Understanding how human neonates respond to infection remains incomplete. Here, a system-level investigation of neonatal systemic responses to infection shows a surprisingly strong but unbalanced homeostatic immune response; developing an elevated set-point of myeloid regulatory signalling and sugar-lipid metabolism with concomitant inhibition of lymphoid responses. Innate immune-negative feedback opposes innate immune activation while suppression of T-cell co-stimulation is coincident with selective upregulation of CD85 co-inhibitory pathways. By deriving modules of co-expressed RNAs, we identify a limited set of networks associated with bacterial infection that exhibit high levels of inter-patient variability. Whereas, by integrating immune and metabolic pathways, we infer a patient-invariant 52-gene-classifier that predicts bacterial infection with high accuracy using a new independent patient population. This is further shown to have predictive value in identifying infection in suspected cases with blood culture-negative tests. Our results lay the foundation for future translation of host pathways in advancing diagnostic, prognostic and therapeutic strategies for neonatal sepsis.
authors.affiliation: 1] Neonatal Unit, Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK [2] Division of Pathway Medicine, Edinburgh Infectious Diseases, University of Edinburgh, Edinburgh EH16 4SB, UK [3].
authors.forename: Claire L
authors.initials: CL
authors.lastname: Smith
authors.affiliation: 1] Division of Pathway Medicine, Edinburgh Infectious Diseases, University of Edinburgh, Edinburgh EH16 4SB, UK [2] SynthSys-Synthetic and Systems Biology, University of Edinburgh, Edinburgh EH9 3JD, UK [3].
authors.forename: Paul
authors.initials: P
authors.lastname: Dickinson
authors.affiliation: 1] Division of Pathway Medicine, Edinburgh Infectious Diseases, University of Edinburgh, Edinburgh EH16 4SB, UK [2] SynthSys-Synthetic and Systems Biology, University of Edinburgh, Edinburgh EH9 3JD, UK.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Forster
authors.affiliation: Division of Pathway Medicine, Edinburgh Infectious Diseases, University of Edinburgh, Edinburgh EH16 4SB, UK.
authors.forename: Marie
authors.initials: M
authors.lastname: Craigon
authors.affiliation: Division of Pathway Medicine, Edinburgh Infectious Diseases, University of Edinburgh, Edinburgh EH16 4SB, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Ross
authors.affiliation: 1] Division of Pathway Medicine, Edinburgh Infectious Diseases, University of Edinburgh, Edinburgh EH16 4SB, UK [2].
authors.forename: Mizanur R
authors.initials: MR
authors.lastname: Khondoker
authors.affiliation: Division of Pathway Medicine, Edinburgh Infectious Diseases, University of Edinburgh, Edinburgh EH16 4SB, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: France
authors.affiliation: 1] Fios Genomics Ltd., ETTC, King's Buildings, Edinburgh EH9 3JL, UK [2].
authors.forename: Alasdair
authors.initials: A
authors.lastname: Ivens
authors.affiliation: 1] Animal Bioscience Research Department, AGRIC, Teagasc, Grange, Dunsany, Co. Meath, Ireland [2].
authors.forename: David J
authors.initials: DJ
authors.lastname: Lynn
authors.affiliation: Neonatal Unit, Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Orme
authors.affiliation: Neonatal Unit, Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK.
authors.forename: Allan
authors.initials: A
authors.lastname: Jackson
authors.affiliation: Division of Pathway Medicine, Edinburgh Infectious Diseases, University of Edinburgh, Edinburgh EH16 4SB, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Lacaze
authors.affiliation: 1] MRC Research Laboratories, Atlantic Boulevard, PO Box 273, Fajara, Gambia [2].
authors.forename: Katie L
authors.initials: KL
authors.lastname: Flanagan
authors.affiliation: Neonatal Unit, Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Stenson
authors.affiliation: 1] Division of Pathway Medicine, Edinburgh Infectious Diseases, University of Edinburgh, Edinburgh EH16 4SB, UK [2] SynthSys-Synthetic and Systems Biology, University of Edinburgh, Edinburgh EH9 3JD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Ghazal
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D001424:Bacterial Infections / Q000276:immunology* / Q000503:physiopathology / Q000517:prevention & control*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology*; D007231:Infant, Newborn; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D053858:Metabolic Networks and Pathways / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology
chemical_list: D015703:Antigens, CD; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D011971:Receptors, Immunologic; D005947:Glucose