title: Rhinovirus-bacteria coexposure synergistically induces CCL20 production from human bronchial epithelial cells.
abstract: Exacerbations of chronic obstructive pulmonary disease are triggered by viral or bacterial pathogens, with human rhinovirus (HRV) and nontypeableHemophilus influenzae(NTHI) among the most commonly detected pathogens. Patients who suffer from concomitant viral and bacterial infection have more severe exacerbations. The airway epithelial cell is the initial site of viral and bacterial interactions, and CCL20 is an epithelial chemokine that attracts immature dendritic cells to the airways and can act as an antimicrobial. As such, it contributes to innate and adaptive immune responses to infection. We used primary cultures of human bronchial epithelial cells and the BEAS-2B cell line to examine the effects of bacterial-viral coexposure, as well as each stimulus alone, on epithelial expression of CXCL8 and, in particular, CCL20. HRV-bacterial coexposure induced synergistic production of CXCL8 and CCL20 compared with the sum of each stimulus alone. Synergistic induction of CCL20 did not require viral replication and occurred with two different HRV serotypes that use different viral receptors. Synergy was also seen with either NTHI orPseudomonas aeruginosaSynergistic induction of CCL20 was transcriptionally regulated. Although NF-κB was required for transcription, it did not regulate synergy, but NF-IL-6 did appear to contribute. Among MAPK inhibitors studied, neither SB203580 nor PD98059 had any effect on synergy, whereas U0126 prevented synergistic induction of CCL20 by HRV and bacteria, apparently via "off-target" effects. Thus bacterial-viral coexposure synergistically increases innate immune responses compared with individual infections. We speculate that this increased inflammatory response leads to worse clinical outcomes.
authors.affiliation: Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Maciejewski
authors.affiliation: Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and.
authors.forename: Kyla C
authors.initials: KC
authors.lastname: Jamieson
authors.affiliation: Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Arnason
authors.affiliation: Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and.
authors.forename: Cora
authors.initials: C
authors.lastname: Kooi
authors.affiliation: Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and.
authors.forename: Shahina
authors.initials: S
authors.lastname: Wiehler
authors.affiliation: Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Traves
authors.affiliation: Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and.|Department of Medicine, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Leigh
authors.affiliation: Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and dproud@ucalgary.ca.
authors.forename: David
authors.initials: D
authors.lastname: Proud
mesh_terms: D001980:Bronchi / Q000473:pathology*; D054418:Chemokine CCL20 / Q000096:biosynthesis* / Q000235:genetics; D003609:Dactinomycin / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology / Q000821:virology*; D006193:Haemophilus influenzae / Q000187:drug effects / Q000502:physiology*; D006367:HeLa Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012229:Rhinovirus / Q000187:drug effects / Q000502:physiology*; D012703:Serotyping; D013997:Time Factors; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: C108355:CCL20 protein, human; D054418:Chemokine CCL20; D006575:Heterocyclic Compounds, 3-Ring; D016328:NF-kappa B; C456319:PS1145; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D003609:Dactinomycin
keywords: antimicrobial immunity; bacteria; chemokines; epithelial cells; rhinovirus