Dysregulation of airway and systemic interferon responses promotes asthma exacerbations in urban children

Courtney L. Gaberino; Matthew C. Altman; Michelle A. Gill; Leonard B. Bacharier; Rebecca S. Gruchalla; George T. O'Connor; Rajesh Kumar; Gurjit K. Khurana Hershey; Meyer Kattan; Andrew H. Liu; Stephen J. Teach; Edward M. Zoratti; Patrice M. Becker; Alkis Togias; Cynthia Visness; James E. Gern; William W. Busse; Daniel J. Jackson

doi:10.1016/j.jaci.2024.12.1090

Dysregulation of airway and systemic interferon responses promotes asthma exacerbations in urban children

Courtney L. Gaberino^*, Matthew C. Altman, Michelle A. Gill, Leonard B. Bacharier, Rebecca S. Gruchalla, George T. O'Connor, Rajesh Kumar, Gurjit K. Khurana Hershey, Meyer Kattan, Andrew H. Liu, Stephen J. Teach, Edward M. Zoratti, Patrice M. Becker, Alkis Togias, Cynthia Visness, James E. Gern, William W. Busse, Daniel J. Jackson

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Background: Determining why some upper respiratory illnesses provoke asthma exacerbations remains an unmet need. Objective: We sought to identify transcriptome-wide gene expression changes associated with colds that progress to exacerbation. Methods: Two hundred eight urban children (6-17 years) with exacerbation-prone asthma were prospectively monitored for up to 2 cold illnesses. Exacerbation illnesses (Ex⁺), defined as colds leading to asthma exacerbations requiring systemic corticosteroids within 10 days, were compared to colds that resolved without exacerbation (Ex⁻). Peripheral blood and nasal lavage samples were collected at baseline and during colds for RNA sequencing. Interferon gene expression was compared between Ex⁺ and Ex⁻ illnesses. Generalized additive modeling revealed interferon response kinetics. Multiple linear regression models compared interferon expression to clinical variables. Results: One hundred six participants were evaluated during 154 colds. There was greater upregulation of differentially expressed interferon genes during Ex⁺ illnesses compared to Ex⁻. Ex⁺ illnesses had greater average and steeper rise in interferon expression. Within 3 days of illness, interferon expression was positively associated with nasal rhinovirus quantity (nasal: adjusted R² = 0.48, P = .015; blood: adjusted R² = 0.22, P = .013), and interferon expression was negatively associated with percentage predicted forced expiratory volume in 1 second (nasal: β = −0.010, P = .048; blood: β = −0.008, P = .023). Participants with lower baseline interferon expression had shorter time to exacerbation, higher risk for exacerbation with viral illnesses, and greater increase in interferon expression during viral colds (nasal: β = −0.80, P < .0001; blood: β = −0.75, P < .0001). Conclusion: Dysregulated interferon responses are important contributors to asthma exacerbation risk in children. Low baseline interferon expression followed by greater upregulation of interferon pathways in airway and blood during respiratory illnesses increased exacerbation risk. Targeting this pathway in at-risk individuals holds promise for the personalized prevention of asthma exacerbations.

Original language	English (US)
Journal	Journal of Allergy and Clinical Immunology
DOIs	https://doi.org/10.1016/j.jaci.2024.12.1090
State	Accepted/In press - 2025

Funding

Supported by National Institutes of Health (NIH)-National Institute of Allergy and Infectious Diseases (NIAID) awards UM1AI160040 awarded to D.J.J and J.E.G., 1UM1AI114271 to W.W.B., and UM2AI117870 to Rho Inc. Additional support was received from UL1TRG01422, Clinical and Translational Science Award (CTSA) UL1TR000150, and UL1TR001422 to J.A.P., 5UL1TR001425 to G.K.K.H., National Center for Research Resources/NIH UL1TR000451 to M.A.G. and R.S.G., Clinical and Translational Science Institute 1UL1TR001430 to G.T.O., CTSA UL1 TR002535 to A.H.L., 5UM1AI114271 to W.W.B. and J.E.G., National Center for Advancing Translational Sciences/NIH UL1 TR001876 to S.J.T., UL1TR002345 to L.B.B and T32AI007635 to C.L.G. P.M.B. and A.T.\u2019s coauthorship of this publication does not constitute an endorsement by the NIH, NIAID, or any other agency of the United States government.

Keywords

Interferon response
molecular pathways
pediatric asthma

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jaci.2024.12.1090

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Gaberino, C. L., Altman, M. C., Gill, M. A., Bacharier, L. B., Gruchalla, R. S., O'Connor, G. T., Kumar, R., Khurana Hershey, G. K., Kattan, M., Liu, A. H., Teach, S. J., Zoratti, E. M., Becker, P. M., Togias, A., Visness, C., Gern, J. E., Busse, W. W., & Jackson, D. J. (Accepted/In press). Dysregulation of airway and systemic interferon responses promotes asthma exacerbations in urban children. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2024.12.1090

@article{9d0e2e7bfb5e4b36babc640c599f12da,

title = "Dysregulation of airway and systemic interferon responses promotes asthma exacerbations in urban children",

abstract = "Background: Determining why some upper respiratory illnesses provoke asthma exacerbations remains an unmet need. Objective: We sought to identify transcriptome-wide gene expression changes associated with colds that progress to exacerbation. Methods: Two hundred eight urban children (6-17 years) with exacerbation-prone asthma were prospectively monitored for up to 2 cold illnesses. Exacerbation illnesses (Ex+), defined as colds leading to asthma exacerbations requiring systemic corticosteroids within 10 days, were compared to colds that resolved without exacerbation (Ex−). Peripheral blood and nasal lavage samples were collected at baseline and during colds for RNA sequencing. Interferon gene expression was compared between Ex+ and Ex− illnesses. Generalized additive modeling revealed interferon response kinetics. Multiple linear regression models compared interferon expression to clinical variables. Results: One hundred six participants were evaluated during 154 colds. There was greater upregulation of differentially expressed interferon genes during Ex+ illnesses compared to Ex−. Ex+ illnesses had greater average and steeper rise in interferon expression. Within 3 days of illness, interferon expression was positively associated with nasal rhinovirus quantity (nasal: adjusted R2 = 0.48, P = .015; blood: adjusted R2 = 0.22, P = .013), and interferon expression was negatively associated with percentage predicted forced expiratory volume in 1 second (nasal: β = −0.010, P = .048; blood: β = −0.008, P = .023). Participants with lower baseline interferon expression had shorter time to exacerbation, higher risk for exacerbation with viral illnesses, and greater increase in interferon expression during viral colds (nasal: β = −0.80, P < .0001; blood: β = −0.75, P < .0001). Conclusion: Dysregulated interferon responses are important contributors to asthma exacerbation risk in children. Low baseline interferon expression followed by greater upregulation of interferon pathways in airway and blood during respiratory illnesses increased exacerbation risk. Targeting this pathway in at-risk individuals holds promise for the personalized prevention of asthma exacerbations.",

keywords = "Interferon response, molecular pathways, pediatric asthma",

author = "Gaberino, {Courtney L.} and Altman, {Matthew C.} and Gill, {Michelle A.} and Bacharier, {Leonard B.} and Gruchalla, {Rebecca S.} and O'Connor, {George T.} and Rajesh Kumar and {Khurana Hershey}, {Gurjit K.} and Meyer Kattan and Liu, {Andrew H.} and Teach, {Stephen J.} and Zoratti, {Edward M.} and Becker, {Patrice M.} and Alkis Togias and Cynthia Visness and Gern, {James E.} and Busse, {William W.} and Jackson, {Daniel J.}",

note = "Publisher Copyright: {\textcopyright} 2025 American Academy of Allergy, Asthma & Immunology",

year = "2025",

doi = "10.1016/j.jaci.2024.12.1090",

language = "English (US)",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

}

Gaberino, CL, Altman, MC, Gill, MA, Bacharier, LB, Gruchalla, RS, O'Connor, GT, Kumar, R, Khurana Hershey, GK, Kattan, M, Liu, AH, Teach, SJ, Zoratti, EM, Becker, PM, Togias, A, Visness, C, Gern, JE, Busse, WW & Jackson, DJ 2025, 'Dysregulation of airway and systemic interferon responses promotes asthma exacerbations in urban children', Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2024.12.1090

TY - JOUR

T1 - Dysregulation of airway and systemic interferon responses promotes asthma exacerbations in urban children

AU - Gaberino, Courtney L.

AU - Altman, Matthew C.

AU - Gill, Michelle A.

AU - Bacharier, Leonard B.

AU - Gruchalla, Rebecca S.

AU - O'Connor, George T.

AU - Kumar, Rajesh

AU - Khurana Hershey, Gurjit K.

AU - Kattan, Meyer

AU - Liu, Andrew H.

AU - Teach, Stephen J.

AU - Zoratti, Edward M.

AU - Becker, Patrice M.

AU - Togias, Alkis

AU - Visness, Cynthia

AU - Gern, James E.

AU - Busse, William W.

AU - Jackson, Daniel J.

PY - 2025

Y1 - 2025

N2 - Background: Determining why some upper respiratory illnesses provoke asthma exacerbations remains an unmet need. Objective: We sought to identify transcriptome-wide gene expression changes associated with colds that progress to exacerbation. Methods: Two hundred eight urban children (6-17 years) with exacerbation-prone asthma were prospectively monitored for up to 2 cold illnesses. Exacerbation illnesses (Ex+), defined as colds leading to asthma exacerbations requiring systemic corticosteroids within 10 days, were compared to colds that resolved without exacerbation (Ex−). Peripheral blood and nasal lavage samples were collected at baseline and during colds for RNA sequencing. Interferon gene expression was compared between Ex+ and Ex− illnesses. Generalized additive modeling revealed interferon response kinetics. Multiple linear regression models compared interferon expression to clinical variables. Results: One hundred six participants were evaluated during 154 colds. There was greater upregulation of differentially expressed interferon genes during Ex+ illnesses compared to Ex−. Ex+ illnesses had greater average and steeper rise in interferon expression. Within 3 days of illness, interferon expression was positively associated with nasal rhinovirus quantity (nasal: adjusted R2 = 0.48, P = .015; blood: adjusted R2 = 0.22, P = .013), and interferon expression was negatively associated with percentage predicted forced expiratory volume in 1 second (nasal: β = −0.010, P = .048; blood: β = −0.008, P = .023). Participants with lower baseline interferon expression had shorter time to exacerbation, higher risk for exacerbation with viral illnesses, and greater increase in interferon expression during viral colds (nasal: β = −0.80, P < .0001; blood: β = −0.75, P < .0001). Conclusion: Dysregulated interferon responses are important contributors to asthma exacerbation risk in children. Low baseline interferon expression followed by greater upregulation of interferon pathways in airway and blood during respiratory illnesses increased exacerbation risk. Targeting this pathway in at-risk individuals holds promise for the personalized prevention of asthma exacerbations.

AB - Background: Determining why some upper respiratory illnesses provoke asthma exacerbations remains an unmet need. Objective: We sought to identify transcriptome-wide gene expression changes associated with colds that progress to exacerbation. Methods: Two hundred eight urban children (6-17 years) with exacerbation-prone asthma were prospectively monitored for up to 2 cold illnesses. Exacerbation illnesses (Ex+), defined as colds leading to asthma exacerbations requiring systemic corticosteroids within 10 days, were compared to colds that resolved without exacerbation (Ex−). Peripheral blood and nasal lavage samples were collected at baseline and during colds for RNA sequencing. Interferon gene expression was compared between Ex+ and Ex− illnesses. Generalized additive modeling revealed interferon response kinetics. Multiple linear regression models compared interferon expression to clinical variables. Results: One hundred six participants were evaluated during 154 colds. There was greater upregulation of differentially expressed interferon genes during Ex+ illnesses compared to Ex−. Ex+ illnesses had greater average and steeper rise in interferon expression. Within 3 days of illness, interferon expression was positively associated with nasal rhinovirus quantity (nasal: adjusted R2 = 0.48, P = .015; blood: adjusted R2 = 0.22, P = .013), and interferon expression was negatively associated with percentage predicted forced expiratory volume in 1 second (nasal: β = −0.010, P = .048; blood: β = −0.008, P = .023). Participants with lower baseline interferon expression had shorter time to exacerbation, higher risk for exacerbation with viral illnesses, and greater increase in interferon expression during viral colds (nasal: β = −0.80, P < .0001; blood: β = −0.75, P < .0001). Conclusion: Dysregulated interferon responses are important contributors to asthma exacerbation risk in children. Low baseline interferon expression followed by greater upregulation of interferon pathways in airway and blood during respiratory illnesses increased exacerbation risk. Targeting this pathway in at-risk individuals holds promise for the personalized prevention of asthma exacerbations.

KW - Interferon response

KW - molecular pathways

KW - pediatric asthma

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UR - http://www.scopus.com/inward/citedby.url?scp=85216668415&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2024.12.1090

DO - 10.1016/j.jaci.2024.12.1090

M3 - Article

C2 - 39788435

AN - SCOPUS:85216668415

SN - 0091-6749

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

ER -

Dysregulation of airway and systemic interferon responses promotes asthma exacerbations in urban children

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Funding

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UN SDGs

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