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Nat Immunol. 2019 May;20(5):637-651. doi: 10.1038/s41590-019-0347-8. Epub 2019 Apr 8.

Transcriptome networks identify mechanisms of viral and nonviral asthma exacerbations in children.

Author information

1
Department of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA. maltman@benaroyaresearch.org.
2
Systems Immunology Program, Benaroya Research Institute, Seattle, WA, USA. maltman@benaroyaresearch.org.
3
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
4
Systems Immunology Program, Benaroya Research Institute, Seattle, WA, USA.
5
Rho, Inc., Chapel Hill, NC, USA.
6
Department of Allergy and Immunology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
7
Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
8
Ann Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
9
Cincinnati Children's Hospital, Cincinnati, OH, USA.
10
Henry Ford Health System, Detroit, MI, USA.
11
Children's National Health System, Washington, DC, USA.
12
Columbia University College of Physicians and Surgeons, New York, NY, USA.
13
Division of Allergy, Immunology, and Pulmonary Medicine, Washington University, St. Louis, MO, USA.
14
Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
15
University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

Abstract

Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations.

PMID:
30962590
PMCID:
PMC6472965
[Available on 2019-10-08]
DOI:
10.1038/s41590-019-0347-8
[Indexed for MEDLINE]

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