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.
Original language | English (US) |
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Pages (from-to) | 637-651 |
Number of pages | 15 |
Journal | Nature Immunology |
Volume | 20 |
Issue number | 5 |
DOIs | |
State | Published - May 1 2019 |
Funding
Competing interests M.A.G. reports consulting fees from the American Academy of Allergy, Asthma, and Immunology and the American Academy of Pediatrics. A.H.L. reports consulting fees from Merck Sharp & Dohme and reports data-monitoring committee membership for an asthma study conducted by GlaxoSmithKline. R.S.G. reports employment as a special government employee with the Center for Biologics Evaluation and Research and consulting fees from the Consulting Massachusetts Medical Society. G.T.O. reports consulting fees from AstraZeneca and reports a grant from Janssen Pharmaceuticals paid to his employing institution. J.A.P. reports provision of study drugs from GlaxoSmithKline, Teva, Merck, Boehringer-Ingelheim, and Genentech/Novartis for research studies outside of the scope of the submitted work. C.M.K. reports consulting fees from GlaxoSmithKline. E.M.Z. reports consulting fees from Wayne State University. S.J.T. reports consulting fees from Novartis, grants from PCORI, the Fight for Children Foundation, EJF Philanthropies, and NIH/NHLBI, and royalties from Uptodate. M.K. reports consulting fees from Novartis. L.B.B. reports consulting fees from Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, Cephalon, DBV Technologies, Teva, Boehringer-Ingelheim, AstraZeneca, WebMD/Medscape, Sanofi, Vectura, and Circassia. J.E.G. reports consulting fees from Janssen, Regeneron, and PReP Biosciences and travel expenses from Boehringer-Ingelheim. W.W.B. reports consulting fees from Boston Scientific, ICON, Novartis, GlaxoSmithKline, Genentech, Roche, Boehringer-Ingelheim, Sanofi Genzyme, AstraZeneca, Teva, 3M, PrEPBiopharm, Circassia, Regeneron, Peptinnovate, and Elsevier. D.J.J. reports consulting fees from Novartis, GlaxoSmithKline, Boehringer-Ingelheim, Pfizer, Commense, and Vectura and a grant from NIH/NHLBI. M.C.A., D.C.B., E.W., B.S., B.J., G.K.K.H., C.C.J., A.B., S.M.S., S.P., P.J.G., L.M.W., and A.T. have nothing to disclose. This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, US Department of Health and Human Services, under contract numbers 1UM1AI114271 awarded to W.W.B. and UM2AI117870 awarded to Rho, Inc. Additional support comes from CTSA UL1TR000150 and UL1TR001422 to J.A.P., 5UL1TR001425 to G.K.K.H., NCRR/NIH UL1TR000451 to M.A.G. and R.S.G., CTSI 1UL1TR001430 to G.T.O., CCTSI UL1TR001082 to A.H.L., 5UM1AI114271 to W.W.B. and J.E.G., NCATS/NIH UL1 TR001876 to S.J.T., and UL1TR002345 to L.B.B. We are grateful to all participants and their families who took part in this study. We thank all of the investigators and staff of the National Institutes of Allergy and Infectious Diseases Inner City Asthma Consortium. We thank the Benaroya Research Institute Genomics and Bioinformatics cores for assistance with sample handling, data generation, and RNA sequencing alignment. We would like to thank P. Woodruff, J. Boyce, and S. Durham for assistance with methodological development as well as advice and discussion.
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology