Personalized Transcriptomics Reveals Heterogeneous Immunophenotypes in Children with Viral Bronchiolitis

Anya C. Jones, Denise Anderson, Sally Galbraith, Emmanuelle Fantino, Diana Gutierrez Cardenas, James F. Read, Michael Serralha, Barbara J. Holt, Deborah H. Strickland, Peter D. Sly, Anthony Bosco, Patrick G. Holt

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 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 Main Results: 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 [erbbb2 receptor tyrosine kinase 2], TGFB1 [transforming growth factor-beta 1], 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.

Original languageEnglish
Pages (from-to)1537-1549
Number of pages13
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume199
Issue number12
DOIs
Publication statusPublished - 15 Jun 2019

Cite this

Jones, Anya C. ; Anderson, Denise ; Galbraith, Sally ; Fantino, Emmanuelle ; Cardenas, Diana Gutierrez ; Read, James F. ; Serralha, Michael ; Holt, Barbara J. ; Strickland, Deborah H. ; Sly, Peter D. ; Bosco, Anthony ; Holt, Patrick G. / Personalized Transcriptomics Reveals Heterogeneous Immunophenotypes in Children with Viral Bronchiolitis. In: American Journal of Respiratory and Critical Care Medicine. 2019 ; Vol. 199, No. 12. pp. 1537-1549.
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title = "Personalized Transcriptomics Reveals Heterogeneous Immunophenotypes in Children with Viral Bronchiolitis",
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 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 Main Results: 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 [erbbb2 receptor tyrosine kinase 2], TGFB1 [transforming growth factor-beta 1], 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.",
keywords = "acute viral bronchiolitis, RNA-Seq, N-of-1-pathways analysis, peripheral blood mononuclear cells, nasal mucosal airways, RESPIRATORY SYNCYTIAL VIRUS, INFLUENZA-VIRUS, CHILDHOOD ASTHMA, INNATE IMMUNITY, CELL RESPONSES, INTERFERON, AIRWAY, INFECTION, EXPRESSION, INFANTS",
author = "Jones, {Anya C.} and Denise Anderson and Sally Galbraith and Emmanuelle Fantino and Cardenas, {Diana Gutierrez} and Read, {James F.} and Michael Serralha and Holt, {Barbara J.} and Strickland, {Deborah H.} and Sly, {Peter D.} and Anthony Bosco and Holt, {Patrick G.}",
year = "2019",
month = "6",
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doi = "10.1164/rccm.201804-0715OC",
language = "English",
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pages = "1537--1549",
journal = "American Journal of Respiratory Critical Care Medicine",
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Personalized Transcriptomics Reveals Heterogeneous Immunophenotypes in Children with Viral Bronchiolitis. / Jones, Anya C.; Anderson, Denise; Galbraith, Sally; Fantino, Emmanuelle; Cardenas, Diana Gutierrez; Read, James F.; Serralha, Michael; Holt, Barbara J.; Strickland, Deborah H.; Sly, Peter D.; Bosco, Anthony; Holt, Patrick G.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 199, No. 12, 15.06.2019, p. 1537-1549.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Personalized Transcriptomics Reveals Heterogeneous Immunophenotypes in Children with Viral Bronchiolitis

AU - Jones, Anya C.

AU - Anderson, Denise

AU - Galbraith, Sally

AU - Fantino, Emmanuelle

AU - Cardenas, Diana Gutierrez

AU - Read, James F.

AU - Serralha, Michael

AU - Holt, Barbara J.

AU - Strickland, Deborah H.

AU - Sly, Peter D.

AU - Bosco, Anthony

AU - Holt, Patrick G.

PY - 2019/6/15

Y1 - 2019/6/15

N2 - 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 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 Main Results: 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 [erbbb2 receptor tyrosine kinase 2], TGFB1 [transforming growth factor-beta 1], 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.

AB - 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 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 Main Results: 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 [erbbb2 receptor tyrosine kinase 2], TGFB1 [transforming growth factor-beta 1], 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.

KW - acute viral bronchiolitis

KW - RNA-Seq

KW - N-of-1-pathways analysis

KW - peripheral blood mononuclear cells

KW - nasal mucosal airways

KW - RESPIRATORY SYNCYTIAL VIRUS

KW - INFLUENZA-VIRUS

KW - CHILDHOOD ASTHMA

KW - INNATE IMMUNITY

KW - CELL RESPONSES

KW - INTERFERON

KW - AIRWAY

KW - INFECTION

KW - EXPRESSION

KW - INFANTS

U2 - 10.1164/rccm.201804-0715OC

DO - 10.1164/rccm.201804-0715OC

M3 - Article

VL - 199

SP - 1537

EP - 1549

JO - American Journal of Respiratory Critical Care Medicine

JF - American Journal of Respiratory Critical Care Medicine

SN - 1073-449X

IS - 12

ER -