Modulation of Human Rhinovirus-Induced Epithelial Responses by Cigarette Smoke

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dc.contributor.advisorProud, David
dc.contributor.authorHudy, Magdalena
dc.date.accessioned2013-07-10T16:49:49Z
dc.date.available2013-11-12T08:00:14Z
dc.date.issued2013-07-10
dc.date.submitted2013en
dc.description.abstractHuman rhinovirus (HRV) is the major viral pathogen associated with exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Cigarette smoke is the predominant risk factor for the development of COPD and approximately 25% of asthmatics smoke. Moreover, smokers experience longer and more severe respiratory tract infections compared to non-smokers, but the mechanisms responsible have not been delineated. Since the airway epithelial cell is the only cell type shown to be infected with HRV in vivo, and is one of the first cells in contact with cigarette smoke, the aim of this thesis was to investigate if and how cigarette smoke modulates epithelial responses to HRV infection using an in vitro tissue culture model system in conjunction with HRV and cigarette smoke extract (CSE). HRV-induced expression of CXCL10, a chemokine linked to antiviral immunity, was potently inhibited by CSE via multiple mechanisms. CSE suppressed HRV-induced transcription of CXCL10 via inhibition of nuclear factor-ĸB (NF-ĸB), interferon regulatory factor (IRF)-1 and signal transducer and activator of transcription (STAT)-1 pathways. CSE also suppressed HRV-induced expression of the viral sensors melanoma differentiation-associated protein 5 (MDA5) and retinoic acid-inducible gene-I (RIG-I), but only MDA5 was shown to be directly involved in HRV-induced CXCL10 production. CSE also suppressed HRV-induced chromatin accessibility around the CXCL10 transcriptional start site. By contrast, epithelial production of the neutrophil chemoattractant CXCL8, was induced by CSE or HRV infection alone, and was further enhanced by the combination of these stimuli. This enhancement was mediated via mRNA stabilization and involved the mRNA stabilizing protein human antigen R (HuR). This study provides the first demonstration that CSE differentially modulates HRV-induced chemokine responses in airway epithelial cells and provides insights into the underlying mechanisms of altered chemokine production. HRV-induced CXCL10 was suppressed by CSE via a combination of multiple mechanisms, while CXCL8 enhancement was mediated via mRNA stabilization. These results provide potential insights into how cigarette smoke alters HRV-induced inflammatory responses in vivo and how this could lead to more severe clinical outcomes in COPD patients and asthmatics who smoke during HRV-induced disease exacerbations.en_US
dc.description.notesA complete paper copy of this thesis is available in the University Archives, http://archives.ucalgary.ca/contact.
dc.identifier.citationHudy, M. (2013). Modulation of Human Rhinovirus-Induced Epithelial Responses by Cigarette Smoke (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/26978en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/26978
dc.identifier.urihttp://hdl.handle.net/11023/781
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectBiology--Cell
dc.subjectBiology--Molecular
dc.subjectImmunology
dc.subject.classificationHuman rhinovirusen_US
dc.subject.classificationCigarette Smokeen_US
dc.subject.classificationAirway epitheliumen_US
dc.subject.classificationInnate immunityen_US
dc.subject.classificationChemokinesen_US
dc.subject.classificationAsthmaen_US
dc.subject.classificationCOPDen_US
dc.titleModulation of Human Rhinovirus-Induced Epithelial Responses by Cigarette Smoke
dc.typedoctoral thesis
thesis.degree.disciplineMedical Science
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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