title: Sequential waves of gene expression in patients with clinically defined dengue illnesses reveal subtle disease phases and predict disease severity.
abstract: BACKGROUND
  Dengue virus (DENV) infection can range in severity from mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Changes in host gene expression, temporally through the progression of DENV infection, especially during the early days, remains poorly characterized. Early diagnostic markers for DHF are also lacking.
  
  
  RESULTS
  In this study, we investigated host gene expression in a cohort of DENV-infected subjects clinically diagnosed as DF (n = 51) and DHF (n = 13) from Maracay, Venezuela. Blood specimens were collected daily from these subjects from enrollment to early defervescence and at one convalescent time-point. Using convalescent expression levels as baseline, two distinct groups of genes were identified: the "early" group, which included genes associated with innate immunity, type I interferon, cytokine-mediated signaling, chemotaxis, and complement activity peaked at day 0-1 and declined on day 3-4; the second "late" group, comprised of genes associated with cell cycle, emerged from day 4 and peaked at day 5-6. The up-regulation of innate immune response genes coincided with the down-regulation of genes associated with viral replication during day 0-3. Furthermore, DHF patients had lower expression of genes associated with antigen processing and presentation, MHC class II receptor, NK and T cell activities, compared to that of DF patients. These results suggested that the innate and adaptive immunity during the early days of the disease are vital in suppressing DENV replication and in affecting outcome of disease severity. Gene signatures of DHF were identified as early as day 1.
  
  
  CONCLUSIONS
  Our study reveals a broad and dynamic picture of host responses in DENV infected subjects. Host response to DENV infection can now be understood as two distinct phases with unique transcriptional markers. The DHF signatures identified during day 1-3 may have applications in developing early molecular diagnostics for DHF.
authors.affiliation: Naval Medical Research Center, Silver Spring, Maryland, USA. peifang.sun@med.navy.mil
authors.forename: Peifang
authors.initials: P
authors.lastname: Sun
authors.forename: Josefina
authors.initials: J
authors.lastname: García
authors.forename: Guillermo
authors.initials: G
authors.lastname: Comach
authors.forename: Maryanne T
authors.initials: MT
authors.lastname: Vahey
authors.forename: Zhining
authors.initials: Z
authors.lastname: Wang
authors.forename: Brett M
authors.initials: BM
authors.lastname: Forshey
authors.forename: Amy C
authors.initials: AC
authors.lastname: Morrison
authors.forename: Gloria
authors.initials: G
authors.lastname: Sierra
authors.forename: Isabel
authors.initials: I
authors.lastname: Bazan
authors.forename: Claudio
authors.initials: C
authors.lastname: Rocha
authors.forename: Stalin
authors.initials: S
authors.lastname: Vilcarromero
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Blair
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Scott
authors.forename: Daria E
authors.initials: DE
authors.lastname: Camacho
authors.forename: Christian F
authors.initials: CF
authors.lastname: Ockenhouse
authors.forename: Eric S
authors.initials: ES
authors.lastname: Halsey
authors.forename: Tadeusz J
authors.initials: TJ
authors.lastname: Kochel
mesh_terms: D000293:Adolescent; D000328:Adult; D002453:Cell Cycle; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003715:Dengue / Q000276:immunology / Q000473:pathology*; D003716:Dengue Virus / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005819:Genetic Markers; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D013997:Time Factors; D014687:Venezuela; D055815:Young Adult
chemical_list: D005819:Genetic Markers