Matthew C Altman1, Stephen R Reeves2, Andrew R Parker3, Elizabeth Whalen4, Kira M Misura5, Kaitlyn A Barrow6, Richard G James6, Teal S Hallstrand7, Steven F Ziegler4, Jason S Debley8. 1. Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Wash; Benaroya Research Institute, Seattle, Wash. 2. Division of Pulmonary and Sleep Medicine, Department of Pediatrics, University of Washington, Seattle, Wash; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Wash. 3. Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Wash. 4. Benaroya Research Institute, Seattle, Wash. 5. Amgen, Inc, Thousand Oaks, Calif. 6. Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Wash. 7. Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, Wash. 8. Division of Pulmonary and Sleep Medicine, Department of Pediatrics, University of Washington, Seattle, Wash; Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Wash. Electronic address: jason.debley@seattlechildrens.org.
Abstract
BACKGROUND: Respiratory viral infection in early childhood, including that from respiratory syncytial virus (RSV), has been previously associated with the development of asthma. OBJECTIVE: We aimed to determine whether ex vivo RSV infection of bronchial epithelial cells (BECs) from children with asthma would induce specific gene expression patterns and whether such patterns were associated with lung function among BEC donors. METHODS: Primary BECs from carefully characterized children with asthma (n = 18) and matched healthy children without asthma (n = 8) were differentiated at an air-liquid interface for 21 days. Air-liquid interface cultures were infected with RSV for 96 hours and RNA was subsequently isolated from BECs. In each case, we analyzed gene expression using RNA sequencing and assessed differences between conditions by linear modeling of the data. BEC donors completed spirometry to measure lung function. RESULTS: RSV infection of BECs from subjects with asthma, compared with uninfected BECs from subjects with asthma, led to a significant increase in expression of 6199 genes. There was significantly greater expression of 195 genes in BECs from children with asthma and airway obstruction (FEV1/forced vital capacity < 0.85 and FEV1 < 100% predicted) than in BECs from children with asthma without obstruction, or in BECs from healthy children. These specific genes were found to be highly enriched for viral response genes induced in parallel with types I and III interferons. CONCLUSIONS: BECs from children with asthma and with obstructive physiology exhibit greater expression of types I and III interferons and interferon-stimulated genes than do cells from children with normal lung function, and expression of interferon-associated genes correlates with the degree of airway obstruction. These findings suggest that an exaggerated interferon response to viral infection by airway epithelial cells may be a mechanism leading to lung function decline in a subset of children with asthma.
BACKGROUND:Respiratory viral infection in early childhood, including that from respiratory syncytial virus (RSV), has been previously associated with the development of asthma. OBJECTIVE: We aimed to determine whether ex vivo RSV infection of bronchial epithelial cells (BECs) from children with asthma would induce specific gene expression patterns and whether such patterns were associated with lung function among BEC donors. METHODS: Primary BECs from carefully characterized children with asthma (n = 18) and matched healthy children without asthma (n = 8) were differentiated at an air-liquid interface for 21 days. Air-liquid interface cultures were infected with RSV for 96 hours and RNA was subsequently isolated from BECs. In each case, we analyzed gene expression using RNA sequencing and assessed differences between conditions by linear modeling of the data. BEC donors completed spirometry to measure lung function. RESULTS:RSV infection of BECs from subjects with asthma, compared with uninfected BECs from subjects with asthma, led to a significant increase in expression of 6199 genes. There was significantly greater expression of 195 genes in BECs from children with asthma and airway obstruction (FEV1/forced vital capacity < 0.85 and FEV1 < 100% predicted) than in BECs from children with asthma without obstruction, or in BECs from healthy children. These specific genes were found to be highly enriched for viral response genes induced in parallel with types I and III interferons. CONCLUSIONS: BECs from children with asthma and with obstructive physiology exhibit greater expression of types I and III interferons and interferon-stimulated genes than do cells from children with normal lung function, and expression of interferon-associated genes correlates with the degree of airway obstruction. These findings suggest that an exaggerated interferon response to viral infection by airway epithelial cells may be a mechanism leading to lung function decline in a subset of children with asthma.
Authors: Y A Bochkov; K M Hanson; S Keles; R A Brockman-Schneider; N N Jarjour; J E Gern Journal: Mucosal Immunol Date: 2009-08-26 Impact factor: 7.313
Authors: Ping Liu; Mohammad Jamaluddin; Kui Li; Roberto P Garofalo; Antonella Casola; Allan R Brasier Journal: J Virol Date: 2006-11-15 Impact factor: 5.103
Authors: Christopher Shelfoon; Sami Shariff; Suzanne L Traves; Cora Kooi; Richard Leigh; David Proud Journal: J Allergy Clin Immunol Date: 2016-02-13 Impact factor: 10.793
Authors: Kim Zomer-Kooijker; Cornelis K van der Ent; Marieke J J Ermers; Cuno S P M Uiterwaal; Maroeska M Rovers; Louis J Bont Journal: PLoS One Date: 2014-01-31 Impact factor: 3.240
Authors: Lyndsey M Muehling; Peter W Heymann; Paul W Wright; Jacob D Eccles; Rachana Agrawal; Holliday T Carper; Deborah D Murphy; Lisa J Workman; Carolyn R Word; Sarah J Ratcliffe; Brian J Capaldo; Thomas A E Platts-Mills; Ronald B Turner; William W Kwok; Judith A Woodfolk Journal: J Allergy Clin Immunol Date: 2020-04-19 Impact factor: 10.793
Authors: Lyndsey M Muehling; Peter W Heymann; Holliday Carper; Deborah D Murphy; Evan Rajadhyaksha; Joshua Kennedy; Stephen V Early; Manuel Soto-Quiros; Lydiana Avila; Lisa Workman; Thomas A E Platts-Mills; Judith A Woodfolk Journal: Clin Exp Allergy Date: 2022-06-06 Impact factor: 5.401
Authors: Gerald G Kellar; Stephen R Reeves; Kaitlyn A Barrow; Jason S Debley; Thomas N Wight; Steven F Ziegler Journal: J Immunol Date: 2020-10-23 Impact factor: 5.422
Authors: Matthew C Altman; Avraham Beigelman; Christina Ciaccio; James E Gern; Peter W Heymann; Daniel J Jackson; Joshua L Kennedy; Kirsten Kloepfer; Robert F Lemanske; Laurie M McWilliams; Lyndsey Muehling; Christy Nance; R Stokes Peebles Journal: J Allergy Clin Immunol Date: 2020-01-09 Impact factor: 14.290
Authors: J D Burleson; Dylan Siniard; Veda K Yadagiri; Xiaoting Chen; Matthew T Weirauch; Brandy P Ruff; Eric B Brandt; Gurjit K Khurana Hershey; Hong Ji Journal: Sci Rep Date: 2019-05-14 Impact factor: 4.379
Authors: Yoshihiko Raita; Marcos Pérez-Losada; Robert J Freishtat; Brennan Harmon; Jonathan M Mansbach; Pedro A Piedra; Zhaozhong Zhu; Carlos A Camargo; Kohei Hasegawa Journal: Nat Commun Date: 2021-06-14 Impact factor: 17.694
Authors: Nathalie J Vielle; Obdulio García-Nicolás; Blandina I Oliveira Esteves; Melanie Brügger; Artur Summerfield; Marco P Alves Journal: Front Microbiol Date: 2019-04-16 Impact factor: 5.640