Gene expression profiling of airway epithelium in Mycobacterium avium complex lung disease

Impaired mucociliary clearance is associated with nontuberculous mycobacterial lung disease (NTM-LD). While airway epithelial cells (AECs), which are essential for maintaining this defence mechanism, play a central role in NTM-LD pathogenesis, their in vivo gene expression in human NTM-LD remains unexplored. We investigated AEC gene expression using surgical specimens of Mycobacterium avium complex lung disease (MAC-LD) patients.

We profiled gene expression of AECs from surgical specimens of age-matched female MAC-LD patients (n=7) and lung cancer patients (n=8), the latter serving as noninfectious controls. Differentially expressed genes identified through weighted gene coexpression network analysis were validated using quantitative reverse transcriptase PCR (qRT‒PCR) in an independent cohort (MAC-LD: n=19, Lung cancer: n=25). Associations between AEC gene expression and MAC-LD clinical phenotypes were also investigated.

We identified 54 upregulated and 4 downregulated genes in AECs from MAC-LD patients. In addition to immune-related genes enriched in antigen presentation, complement and coagulation cascades, neutrophil migration and the interleukin-17 signalling pathway, SLC26A4, which encodes the anion exchanger pendrin, was markedly upregulated (log₂ fold change of 3.0, false discovery rate of 0.8×10^-5). The increased expression of the selected genes CCL20, MMP9, C3 and SLC26A4 was validated, and their reproducibility was confirmed in the validation cohort. Among the 26 MAC-LD patients, the AEC gene expression level of MMP9 was significantly elevated in patients with cavitary lesions, whereas SLC26A4 expression was correlated with bronchiectasis severity.

SLC26A4, an anion exchanger, was markedly upregulated in MAC-LD AECs, alongside various immune-related genes. The associations between gene expression and key disease phenotypes suggest potential targets for novel therapeutics.