Mapping a Mouse Model of Severe Asthma to Human Asthma Using Gene Set Variation Analysis

Animal models of asthma do not always translate to human disease. To improve translation, we used transcriptomic profiles and gene set variation analysis (GSVA) to map a mouse model of severe asthma to the U-BIOPRED human cohorts. Mice were sensitised with house dust mite (HDM) in complete Freunds adjuvant for 2 weeks before challenge with HDM. Lung tissue was collected post challenge and gene expression analysed performed. There were 167, 798, 385 and 129 differentially up-regulated (FDR<0.01) genes for days 1, 3, 4 and 7 respectively. There were 26 common up-regulated genes at each time point (CCL26,POSTN,ITGB2) that are associated with cytokine, chemokine and integrin signalling, this was used as a GSVA gene signature. The gene signature was used to map the mouse severe asthma model to U-BIOPRED cohort. Enrichment of this signature in blood, biopsy, bronchial brushing, sputum and nasal brushings from all cohorts were analysed. There was significant enrichment of the signature in severe non-smoking asthma (a) compared to healthy subjects (d) in biopsies, bronchial brushings and sputum samples. This was not significantly different in non-severe asthma. The mouse gene signature showed significant upregulation in human severe non-smoking asthma. This approach may be used to investigate whether other models of severe asthma align with human disease with the model selection dependent on the subset of disease being investigated.