Airway epithelial gene expression unveils the pathogenesis of Mycobacterium avium complex lung disease

<bold>Rationale:</bold> Impaired mucociliary clearance is associated with nontuberculous mycobacterial lung disease (NTM-LD). However, the role of airway epithelial cells (AECs), essential for mucociliary clearance, antigen presentation, and antimicrobial peptide production, in NTM-LD is unclear. This study explores AECs' role in <italic>Mycobacterium avium</italic> complex lung disease (MAC-LD) through gene expression analysis. <bold>Methods:</bold> We compared gene-expression profiling of AECs of age-matched female MAC-LD (n=7) and lung cancer patients (n=8) who underwent lung resection. AECs were collected from the large bronchi of the resected lungs for RNA-sequencing. Differential gene expression was assessed using DESeq2. RT-qPCR was performed to validate the expression levels of selected genes using the external cohort (MAC-LD 19 vs Lung cancer 25 samples). <bold>Results:</bold> We identified 54 up-regulated and 4 down-regulated differentially expressed genes in MAC-LD AECs compared to lung cancer. Enrichment analysis showed that genes involved in immune response, including antigen presentation, neutrophil migration, and Th17 cell differentiation, were notably enhanced in MAC-LD AECs. The increased expressions of the selected genes, CCL20, MMP9 and C3, were verified and validated in the external cohort by RT-qPCR. Gene expressions of C3 and MMP9 in MAC-LD AECs were related to the presence of cavitary lesions. <bold>Conclusions:</bold> AECs in MAC-LD is involved in the immune response, through antigen presentation and induction of neutrophilic migration and activation. The study reveals the association of C3 and MMP9 expressions in AECs with cavitary lesions, offering insights into pathogenesis and cavitation process.