title: Systems immunology reveals markers of susceptibility to West Nile virus infection.
abstract: West Nile virus (WNV) infection is usually asymptomatic but can cause severe neurological disease and death, particularly in older patients, and how individual variations in immunity contribute to disease severity is not yet defined. Animal studies identified a role for several immunity-related genes that determine the severity of infection. We have integrated systems-level transcriptional and functional data sets from stratified cohorts of subjects with a history of WNV infection to define whether these markers can distinguish susceptibility in a human population. Transcriptional profiles combined with immunophenotyping of primary cells identified a predictive signature of susceptibility that was detectable years after acute infection (67% accuracy), with the most prominent alteration being decreased IL1B induction following ex vivo infection of macrophages with WNV. Deconvolution analysis also determined a significant role for CXCL10 expression in myeloid dendritic cells. This systems analysis identified markers of pathogenic mechanisms and offers insights into potential therapeutic strategies.
authors.affiliation: Section of Rheumatology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Goel
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Hailong
authors.initials: H
authors.lastname: Meng
authors.affiliation: Section of Rheumatology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Section of Infectious Disease, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Fuping
authors.initials: F
authors.lastname: You
authors.affiliation: Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Lesley
authors.initials: L
authors.lastname: Devine
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Khadir
authors.initials: K
authors.lastname: Raddassi
authors.affiliation: Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Melissa N
authors.initials: MN
authors.lastname: Garcia
authors.affiliation: Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Kristy O
authors.initials: KO
authors.lastname: Murray
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Bolen
authors.affiliation: Department of Immunology, Rappaport Institute of Medical Research, Faculty of Medicine and Faculty of Biology, Technion, Haifa, Israel.
authors.forename: Renaud
authors.initials: R
authors.lastname: Gaujoux
authors.affiliation: Department of Immunology, Rappaport Institute of Medical Research, Faculty of Medicine and Faculty of Biology, Technion, Haifa, Israel.
authors.forename: Shai S
authors.initials: SS
authors.lastname: Shen-Orr
authors.affiliation: Department of Neurology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hafler
authors.affiliation: Section of Infectious Disease, Yale School of Medicine, New Haven, Connecticut, USA Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Erol
authors.initials: E
authors.lastname: Fikrig
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Ramnik
authors.initials: R
authors.lastname: Xavier
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Yale School of Medicine, New Haven, Connecticut, USA Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
authors.affiliation: Section of Rheumatology, Yale School of Medicine, New Haven, Connecticut, USA ruth.montgomery@yale.edu.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Montgomery
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000276:immunology; D004198:Disease Susceptibility; D005260:Female; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006801:Humans; D016130:Immunophenotyping; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D049490:Systems Biology / Q000379:methods*; D014158:Transcription, Genetic; D014902:West Nile virus / Q000276:immunology*; D055815:Young Adult
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D005819:Genetic Markers; D053583:Interleukin-1beta