Saturday, May 31, 2025
5/31/2025
The role of Alternaria fungal sensitization in asthma pathogenesis - PROJECT SUMMARY ALTernaria ALTernata (ALT) is the most common outdoor airborne fungus found worldwide. The prevalence of ALT sensitization ranges from 2% to 23.8% in the general population and much higher among asthmatics. ALT sensitization has been associated with airway hyper-responsiveness, asthma and adverse asthma outcomes. It is an enigma why some people develop sensitization to a common fungal allergen (ALT) while others don’t. Moreover, the reason why ALT sensitization is associated with increased risk of developing asthma is not known. In this proposal, we will explore the mechanisms and cell types that drive ALT sensitization and the development of asthma. We recently identified a novel subset of house dust mite (HDM)-specific T cells characterized by an interferon response (IFNR) gene signature (THIFNR cells), which was negatively associated with HDM sensitization. In a pilot study, focussed in ALT allergen, we found that the proportion of ALT-specific THIFNR cells was increased in healthy subjects without ALT sensitization when compared to asthmatic subjects suggesting that it may also play a protective role in ALT-sensitization and asthma. We also found that ALT-specific TH2 cells from asthmatics displayed pathogenic features that were distinct from HDM- specific TH2 cells. Based on these findings, we hypothesize that ALT-specific THIFNR cells protect against ALT-sensitization in healthy subjects, and a novel pathogenic TH2 subset in the airways, specifically tissue- resident memory T cells (TRM cells) promote the development of asthma in ALT sensitized subjects. In Aim 1, we will determine the association between ALT-specific THIFNR cells and protection against ALT sensitization. We will assess subjects enrolled in the Isle of Wight Whole Population Birth Cohort. We will identify subgroups of participants (n=100) with: (i) Persistent ALT-sensitization since childhood (n=25), (ii) Adult-onset ALT- sensitization (n=25), (iii) HDM-sensitized without ALT-sensitization since childhood (n=25), and (iv) Non- atopic since childhood (n=25). We will isolate ALT-specific T cells from blood and perform single-cell RNA-seq and TCR-seq to enumerate the frequency, properties, persistence and clonality of ALT-specific T cell subsets, including the novel THIFNR cell subpopulation, and determine their association with risk and protection against development of ALT-sensitization at different ages. In Aim 2, we will identify ALT-specific T cell subsets in the blood and airways associated with the development of asthma in subjects with ALT-sensitization. We will enroll 50 subjects with ALT-sensitization from the IOWBC (n=25 with asthma, n=25 without asthma), and as controls, 50 asthmatic subjects without ALT-sensitization (n=25 with HDM- sensitization, and n=25 with no sensitization to common allergens), obtain blood and airway samples (sputum). We will perform single-cell transcriptome and TCR-seq analysis to determine the frequency, properties, persistence and clonality of ALT-specific TH cell and TRM subsets in the blood and airways, and their association with asthma.
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