B17-03 T-helper 1 Transcriptomic Profile Is Associated With Viral Abundance in Nasal Epithelium From Youths With Asthma

Rationale Asthma is a heterogeneous disease comprising distinct endotypes, including T helper (T)2-high and T17-high asthma. We previously identified three nasal epithelial transcriptomic profiles corresponding to 3 endotypes (T2-high, T17-high, and T2-low/T17-low) in youths with asthma. Building on this, we hypothesized that these endotypes could be refined by adding T1 “signature genes” to our panel, and that T1-high profiles would be associated with increased viral abundance. Methods We analyzed nasal epithelial RNA-seq data from four cohorts of youths with asthma, aged 6 to 20 years: TOPMAS (n = 92), STAR (n = 156), EVA-PR (n = 237), and VDKA (n = 66). Clustering was performed using expression levels of 13 “signature genes” for T1, T2, and T17 inflammatory markers, and clinical and demographic characteristics were then compared across transcriptomic profiles. Differential expression meta-analysis and weighted gene co-expression network analysis (WGCNA) were conducted to identify pathways and gene modules. Viral metagenomics analyses were performed using the nf-core tax-profiler pipeline, and deconvolution was used to estimate cell type composition in nasal samples. Results Five transcriptomic profiles were consistently identified across all studies: T2-high, T17-high, T1-high, T1-high/T17-high, and T1-low/T2-low/T17-low (Figure, Panel A). The prevalence of T1-high profiles ranged from 9-20% across cohorts (Panel B). Compared to T1-low profiles, the T1-high profile had 734 upregulated genes, including WARS, GBP4, GBP5, and GZMB (Panel C). Pathway enrichment analysis identified interferon gamma signaling, antigen presentation, and Th1 activation pathways (Panel D). WGCNA modules associated with the T1-high profile were enriched in viral response and cytokine regulation pathways. Viral abundance was significantly higher in T1-high profiles than in T1-low profiles (meta-analysis standardized mean difference=0.26; 95% CI, 0.05-0.46). Differential abundance analysis identified taxa enriched in T1-high profiles, including Actinomyces, Veillonella, and Mycobacterium. Deconvolution analysis showed higher proportions of activated squamous, club, myeloid, antigen presenting, and T cells in T1-high than in T1-low profiles. Conclusions By incorporating T1-signature genes into nasal transcriptomic profiling, we identified a novel T1-high asthma endotype in youths across four diverse cohorts. This endotype was consistently associated with increased viral abundance and distinct transcriptomic pathways related to antiviral immunity. Our findings refine the classification of pediatric T2-low asthma and suggest potential therapeutic targets for T1-driven inflammation. This abstract is funded by: NIH