Enhanced Induction of Epithelial-Derived IL-17C Following Bacteria and Rhinovirus Exposure

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dc.contributor.advisorProud, David
dc.contributor.authorJamieson, Kyla Carol
dc.contributor.committeememberJenne, Craig N.
dc.contributor.committeememberHirota, Simon Andrew
dc.contributor.committeememberYipp, Bryan G.
dc.contributor.committeememberMcCoy, Kathy D.
dc.contributor.committeememberPeebles, Ray Stokes
dc.date2019-11
dc.date.accessioned2019-05-21T14:41:40Z
dc.date.available2019-05-21T14:41:40Z
dc.date.issued2019-05-15
dc.description.abstractUp to 80% of Chronic Obstructive Pulmonary Disease (COPD) exacerbations are associated with bacterial and/or viral pathogens, with bacteria-virus co-infections detected in up to 25% of exacerbations. These co-infections are associated with increased symptoms, increased systemic inflammation, longer hospital stays, and increased risk of hospital re-admission. Human rhinovirus (HRV) is the most common viral pathogens detected, while non-typeable Haemophilus influenzae (NTHI) and Pseudomonas aeruginosa (PAO) are among the most common bacterial pathogens identified. The airway epithelium is the first line of defence against these pathogens and responds by releasing proinflammatory cytokines and anti-microbial peptides. Interleukin (IL)-17C is a novel pro-inflammatory cytokine that is typically released from epithelial cells in response to bacteria, viral, or fungal pathogens, and in response to pro-inflammatory cytokines such as TNFα and IL-1β. In this thesis, we performed the first study to assess the involvement and functional role of IL-17C in bacteria-rhinovirus co-infections in human bronchial epithelial cells (HBECs). Bacteria-rhinovirus co-exposure for 24 hours induced significant, and synergistic, IL-17C gene expression and protein release. Synergistic IL-17C release was dependent on viral replication recognition sensors, RIG-I and MDA5, as well as NF-κB and p38 signalling. In an autocrine/paracrine manner, IL-17C acted on the airway epithelium to induce CXCL1, CXCL2, TFRC, and NFKBIZ gene expression, to induce CXCL1 protein release, and to promote HBEC-induced neutrophil recruitment. To assess how IL-17C is involved in the clinical context of COPD, HBECs were obtained via bronchial brushings from non-smokers, smokers with normal lung function, and patients with physician-diagnosed COPD and these cells were exposed to NTHI and HRV-1A concurrently. Interestingly, in response to concurrent NTHI and HRV-1A exposure, HBECs from COPD patients released significantly more IL-17C than cells from either non-smokers or healthy smokers, and HBECs from healthy smokers released significantly less IL-17C than non-smokers. Further, acute cigarette smoke extract exposure significantly reduced microbial-induced IL-17C release from cells from normal subjects. Using a morphologically-relevant well-differentiated HBEC model, IL-17C was predominantly released basolaterally, from apical cells, in response to HRV in a dose-, time-, and replication-dependent manner. High doses of NTHI could also induce basolateral IL-17C, however synergy was no longer achieved with NTHI+HRV-1A co-infections. Similar to monolayer culture, IL-17C acted on basal cells to induce significant basolateral release of CXCL1, providing physiological relevance for subsequent neutrophil recruitment. These results suggest that IL-17C acts to induce CXCL1 release and promote neutrophil recruitment to the site of bacteria or rhinovirus respiratory infections, however, this response is exaggerated in epithelial cells from COPD patients.en_US
dc.identifier.citationJamieson, K. C. (2019). Enhanced Induction of Epithelial-Derived IL-17C Following Bacteria and Rhinovirus Exposure (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/36543
dc.identifier.urihttp://hdl.handle.net/1880/110374
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
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.en_US
dc.subjectrhinovirusen_US
dc.subjectbacteriaen_US
dc.subjectlung infectionsen_US
dc.subjectCOPDen_US
dc.subjectneutrophil chemotaxisen_US
dc.subjectIL-17Cen_US
dc.subjectairway epitheliumen_US
dc.subjectcigarette smokeen_US
dc.subjectair-liquid interfaceen_US
dc.subject.classificationBiology--Cellen_US
dc.subject.classificationMicrobiologyen_US
dc.subject.classificationVirologyen_US
dc.subject.classificationImmunologyen_US
dc.titleEnhanced Induction of Epithelial-Derived IL-17C Following Bacteria and Rhinovirus Exposureen_US
dc.typedoctoral thesisen_US
thesis.degree.disciplineMedicine – Cardiovascular/Respiratory Scienceen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameDoctor of Philosophy (PhD)en_US
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