Airway pathogens and immune responses in severe asthma

Thesis

Asthma is a heterogenous, chronic inflammatory disease of the airways, and the world’s most common chronic lung disease. Ten percent of patients have airways inflammation resistant to inhaled corticosteroid therapy. I explored several treatable traits amongst these patients. First, the airway microbiome is more likely to be altered and dominated by pathogenic bacteria in these patients, driving symptoms, asthma attack risk and steroid resistant neutrophilic airways inflammation. The nature of this problem had not been fully defined. However, the macrolide azithromycin, which has antimicrobial and anti-inflammatory properties is an effective targeted therapy but is associated with antimicrobial resistance and the dominant mechanism was unknown. A second group of patients with treatment resistant disease is characterised by severe type-2 inflammation and high levels of the biomarker fractional exhaled nitric oxide.

I performed a metagenomic study using Nanopore sequencing, which found a dominant pathogen in 20-30% of adults with severe asthma associated with neutrophilic inflammation. I undertook a mechanistic interventional bronchoscopy study of azithromycin in 10 patients meeting clinical criteria for treatment. Using single cell sequencing I identified both antibacterial and anti-inflammatory effects of azithromycin, making it effective in the presence or absence of infection. Azithromycin supports recovery and normal functioning of the airway epithelium and secretory cells, shapes innate immune responses by neutrophils and macrophages, dampening overzealous responses which could cause tissue damage, whilst inducing a quiescent state in airway T cells which upregulate mediators involved in tissue repair. I demonstrate the microbiome and cellular composition of the upper and lower airway are very distinct. I characterised T cells in a second, larger, single cell bronchoscopy study of 43 participants with severe asthma and health. This unique resource constitutes the largest single cell dataset in severe asthma to date, with which I will explore mechanisms driving corticosteroid resistant disease.

Authors: Jabeen, MF

• DOI: 10.5287/ora-2zq8y8exw
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: microbiome; single cell sequencing; severe asthma
• Subjects: Infection; Immunology; Asthma