Targeting Antiviral Mechanisms in Asthma: Pharmacological Modulation of Epithelial Viral Sensing
Malm Tillgren, Sofia LU
(2026)
In Lund University, Faculty of Medicine Doctoral Dissertation Series
- Abstract
- Asthma is a heterogeneous chronic respiratory disease affecting millions worldwide, and the prevalence is increasing. Although most patients achieve disease control using mainstay treatment with inhaled corticosteroids and bronchodilators, a subgroup of patients suffers from uncontrolled disease. Developing novel therapeutic strategies for these patients is therefore of great importance.
When treatment is insufficient, patients may experience an acute worsening of symptoms, known as asthma exacerbations. These episodes are triggered by various environmental factors, with rhinovirus (RV) infections being the most common cause.
RV primarily targets the bronchial epithelium, which functions both as a physical barrier and as an... (More) - Asthma is a heterogeneous chronic respiratory disease affecting millions worldwide, and the prevalence is increasing. Although most patients achieve disease control using mainstay treatment with inhaled corticosteroids and bronchodilators, a subgroup of patients suffers from uncontrolled disease. Developing novel therapeutic strategies for these patients is therefore of great importance.
When treatment is insufficient, patients may experience an acute worsening of symptoms, known as asthma exacerbations. These episodes are triggered by various environmental factors, with rhinovirus (RV) infections being the most common cause.
RV primarily targets the bronchial epithelium, which functions both as a physical barrier and as an initiator of antiviral immune responses. In asthma, the bronchial epithelial function is dysregulated, characterized by barrier impairment, overproduction of epithelial alarmins and deficient production of antiviral interferons. This thesis aimed to investigate how pharmacological agents modulate altered immune mechanisms in the asthmatic bronchial epithelium. In addition, we aimed to assess pulmonary immune responses in commonly used inbred mouse strains in response to a viral mimic.
We demonstrate that imiquimod, a TLR7 agonist, suppresses the poly(I:C) (a viral replication mimic)-induced pro-inflammatory and alarmin responses, while enhancing antiviral signaling in bronchial epithelial cells (BECs) from patients with asthma. We also demonstrate that following three days of intranasal poly(I:C) administration, BALB/c and C57Bl/6J, but not C57Bl/6N, mice show upregulation of general inflammatory markers in the lung, identifying them as suitable models for studying antiviral immune responses in the lung. Furthermore, we show that azithromycin, a macrolide antibiotic, enhances antiviral signaling in BECs from patients with asthma regardless of clinical asthma phenotype, via the TBK1/IKKε-IRF3/IRF7 axis. Interestingly, a macrolide with negligible antimicrobial activity showed similar effects, suggesting that the antiviral effects of azithromycin are independent of its antimicrobial activity.
This thesis sheds light on different pharmacological approaches to normalizing altered immune mechanisms in the asthmatic bronchial epithelium and broadens our understanding of the immunomodulatory mechanisms of macrolide antibiotics.
(Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/bb68a966-8167-485a-a8e0-bbbec09e8495
- author
- Malm Tillgren, Sofia
LU
- supervisor
- opponent
-
- Clinical Associate Professor Singanayagam, Aran, Imperial Collage, London
- organization
- publishing date
- 2026
- type
- Thesis
- publication status
- published
- subject
- keywords
- Asthma, Rhinovirus, Epithelial cells, Asthma, Asthma exacerbation, Rhinovirus, imiquimod, azithromycin, antiviral defense
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2026:16
- edition
- 2026:16
- pages
- 72 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/69340084417
- defense date
- 2026-02-12 09:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-814-6
- language
- English
- LU publication?
- yes
- id
- bb68a966-8167-485a-a8e0-bbbec09e8495
- date added to LUP
- 2026-01-15 08:30:34
- date last changed
- 2026-01-29 12:48:24
@phdthesis{bb68a966-8167-485a-a8e0-bbbec09e8495,
abstract = {{Asthma is a heterogeneous chronic respiratory disease affecting millions worldwide, and the prevalence is increasing. Although most patients achieve disease control using mainstay treatment with inhaled corticosteroids and bronchodilators, a subgroup of patients suffers from uncontrolled disease. Developing novel therapeutic strategies for these patients is therefore of great importance. <br/>When treatment is insufficient, patients may experience an acute worsening of symptoms, known as asthma exacerbations. These episodes are triggered by various environmental factors, with rhinovirus (RV) infections being the most common cause. <br/>RV primarily targets the bronchial epithelium, which functions both as a physical barrier and as an initiator of antiviral immune responses. In asthma, the bronchial epithelial function is dysregulated, characterized by barrier impairment, overproduction of epithelial alarmins and deficient production of antiviral interferons. This thesis aimed to investigate how pharmacological agents modulate altered immune mechanisms in the asthmatic bronchial epithelium. In addition, we aimed to assess pulmonary immune responses in commonly used inbred mouse strains in response to a viral mimic. <br/>We demonstrate that imiquimod, a TLR7 agonist, suppresses the poly(I:C) (a viral replication mimic)-induced pro-inflammatory and alarmin responses, while enhancing antiviral signaling in bronchial epithelial cells (BECs) from patients with asthma. We also demonstrate that following three days of intranasal poly(I:C) administration, BALB/c and C57Bl/6J, but not C57Bl/6N, mice show upregulation of general inflammatory markers in the lung, identifying them as suitable models for studying antiviral immune responses in the lung. Furthermore, we show that azithromycin, a macrolide antibiotic, enhances antiviral signaling in BECs from patients with asthma regardless of clinical asthma phenotype, via the TBK1/IKKε-IRF3/IRF7 axis. Interestingly, a macrolide with negligible antimicrobial activity showed similar effects, suggesting that the antiviral effects of azithromycin are independent of its antimicrobial activity. <br/>This thesis sheds light on different pharmacological approaches to normalizing altered immune mechanisms in the asthmatic bronchial epithelium and broadens our understanding of the immunomodulatory mechanisms of macrolide antibiotics. <br/>}},
author = {{Malm Tillgren, Sofia}},
isbn = {{978-91-8021-814-6}},
issn = {{1652-8220}},
keywords = {{Asthma; Rhinovirus; Epithelial cells; Asthma; Asthma exacerbation; Rhinovirus; imiquimod; azithromycin; antiviral defense}},
language = {{eng}},
number = {{2026:16}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Targeting Antiviral Mechanisms in Asthma: Pharmacological Modulation of Epithelial Viral Sensing}},
url = {{https://lup.lub.lu.se/search/files/239561015/Sofia_Malm_Tillgren_WEB.pdf}},
year = {{2026}},
}