Personalized Transcriptomics Reveals Heterogeneous Immunophenotypes in Children with Viral Bronchiolitis.
Am J Respir Crit Care Med
; 199(12): 1537-1549, 2019 06 15.
Article
in En
| MEDLINE
| ID: mdl-30562046
ABSTRACT
Rationale A subset of infants are hypersusceptible to severe/acute viral bronchiolitis (AVB), for reasons incompletely understood. Objectives:
To characterize the cellular/molecular mechanisms underlying infant AVB in circulating cells/local airway tissues.Methods:
Peripheral blood mononuclear cells and nasal scrapings were obtained from infants (<18 mo) and children (≥18 mo to 5 yr) during AVB and after convalescence. Immune response patterns were profiled by multiplex analysis of plasma cytokines, flow cytometry, and transcriptomics (RNA-Seq). Molecular profiling of group-level data used a combination of upstream regulator and coexpression network analysis, followed by individual subject-level data analysis using personalized N-of-1-pathways methodology. Measurements and MainResults:
Group-level analyses demonstrated that infant peripheral blood mononuclear cell responses were dominated by monocyte-associated hyperupregulated type 1 IFN signaling/proinflammatory pathways (drivers TNF [tumor necrosis factor], IL-6, TREM1 [triggering receptor expressed on myeloid cells 1], and IL-1B), versus a combination of inflammation (PTGER2 [prostaglandin E receptor 2] and IL-6) plus growth/repair/remodeling pathways (ERBB2 [erbb-b2 receptor tyrosine kinase 2], TGFB1 [transforming growth factor-ß1], AREG [amphiregulin], and HGF [hepatocyte growth factor]) coupled with T-helper cell type 2 and natural killer cell signaling in children. Age-related differences were not attributable to differential steroid usage or variations in underlying viral pathogens. Nasal mucosal responses were comparable qualitatively in infants/children, dominated by IFN types 1-3, but the magnitude of upregulation was higher in infants (range, 6- to 48-fold) than children (5- to 17-fold). N-of-1-pathways analysis confirmed differential upregulation of innate immunity in infants and natural killer cell networks in children, and additionally demonstrated covert AVB response subphenotypes that were independent of chronologic age.Conclusions:
Dysregulated expression of IFN-dependent pathways after respiratory viral infections is a defining immunophenotypic feature of AVB-susceptible infants and a subset of children. Susceptible subjects seem to represent a discrete subgroup who cluster based on (slow) kinetics of postnatal maturation of innate immune competence.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phenotype
/
Leukocytes, Mononuclear
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Bronchiolitis, Viral
/
Transcriptome
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Immunity, Innate
/
Nasal Mucosa
Limits:
Child, preschool
/
Female
/
Humans
/
Infant
/
Male
/
Newborn
Language:
En
Journal:
Am J Respir Crit Care Med
Journal subject:
TERAPIA INTENSIVA
Year:
2019
Type:
Article