On causes and regulation of anti-viral defence in asthma and COPD

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Rhinovirus infection is a main trigger of asthma and COPD exacerbations. dsRNA, a viral replication intermediate, is sensed by pattern recognition receptors in the airway epithelium leading to down-stream induction of anti-viral interferons. Several studies have demonstrated that the rhinoviral-induced interferon response can be deficient in asthmatics, possibly resulting in more severe and lengthened exacerbations. The mechanisms underlying the impaired interferon response are not well understood.
The aim of this thesis was to investigate molecular pathways that could be involved in the regulation of interferons and explore pharmacological interventions to augment anti-viral defences. We employed both in vitro primary bronchial epithelial cell cultures of healthy donors and patients with asthma and COPD and in vivo mouse models of viral stimulus-induced asthma exacerbations.
Our results demonstrate a role for the inflammasome in Th2 inflammation including the induction of Th2-upstream cytokines IL-33, TSLP and IL-25 in a mouse model of viral stimulus-induced asthma exacerbation. Inflammasome activation might be mediated by reactive oxygen species. Here we show that an excess of reactive oxygen species, termed oxidative stress, induced by pre-treatment with H2O2 impairs anti-viral responses in vitro in poly(I:C)-stimulated bronchial epithelial cells of COPD patients and asthmatics. Release of reactive oxygen species can also be triggered by proteolytic allergens, such as house dust mite. Previous exposure to allergens can amplify symptoms of viral-induced asthma exacerbations but the mechanisms behind this interplay are largely unknown. Here we demonstrate that stimulation of bronchial epithelial cells with house dust mite prior to exposure to poly(I:C) reduces IFNß and expression of the pattern recognition receptors TLR3, RIG-I and MDA5. This was also confirmed in our mouse model of viral stimulus-induced asthma exacerbation. Heat-inactivation of house dust mite largely restored anti-viral responses. Our results show that house dust mite likely exerts its action on anti-viral signalling by affecting glycosylation of TLR3. Despite pharmacological interventions patients still continue to experience exacerbations and novel treatment approaches are warranted. Here we find that azithromycin, a macrolide antibiotic, augments rhinovirus-induced IFNß expression in bronchial epithelial cells of both asthma and COPD donors but not healthy volunteers. This was associated with enhanced levels of the pattern recognition receptors MDA5 and RIG-I and reduced viral load. In our mouse model of viral stimulus-induced asthma exacerbation azithromycin restored reduced IFNß levels in exacerbating mice to those of non-allergic mice. Azithromycin possibly exerts its anti-viral actions by activation of MDA5.
In conclusion, our findings show that several pathways might affect interferon expression. Targeting these signalling pathways by pharmaceutical intervention could boost interferon production and thus lower the burden of exacerbations. Azithromycin presents as such a possible drug opportunity but requires further clinical investigation.

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Research areas and keywords

Keywords

  • asthma, chronic obstructive pulmonary disease, rhinovirus, exacerbation, airway epithelial cell, pattern recognition receptors, interferon, allergen, azithromycin, inflammasome, epithelial-derived cytokines, oxidative stress
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2018 Sep 28
Place of PublicationLund
Publisher
  • Lund University, Faculty of Medicine
Print ISBNs978-91-7619-673-1
Publication statusPublished - 2018
Publication categoryResearch

Bibliographic note

Defence details Date: 2018-09-28 Time: 09:00 Place: Rune Grubb salen, BMC I1145, Sölvegatan 19 i Lund External reviewer(s) Name: Edwards, Michael Title: Dr Affiliation: Imerial College, London, UK

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