NONTUBERCULOUS mycobacterial lung disease may be shaped by airway inflammation, disease severity, and infection duration.
New ATS 2026 findings suggest that immune activity in the lower airways of patients with nontuberculous mycobacterial lung disease may be driven not only by infection, but also by the severity and persistence of underlying lung disease. The results point to a Th17 and neutrophilic inflammatory signature that could help guide future host-directed treatment strategies.
Nontuberculous mycobacterial lung disease often occurs in people with chronic pulmonary conditions such as bronchiectasis, where prolonged treatment courses and variable outcomes create a need for additional therapeutic approaches. To better understand the host response, researchers analyzed bronchoalveolar lavage fluid samples from 200 people undergoing clinically indicated bronchoscopies, 46% of whom were NTM positive.
Disease severity was assessed using the Bronchiectasis Severity Index in 182 participants. Of these, 60 had low scores, 81 had moderate scores, and 41 had severe scores.
Disease Severity Drives Gene Changes
Host transcriptome analysis identified more than 1,500 differentially enriched genes in participants with severe disease, regardless of NTM status. This finding suggests that lower airway biology may reflect the broader burden of bronchiectasis and airway damage, rather than the presence of NTM alone.
Pathway analysis showed upregulation of PI3K/AKT, neutrophil degranulation, neutrophil extracellular trap formation, IL-17, IL-1, and MAP kinase pathways in participants with severe disease. These signals were present in the full cohort and among NTM-positive participants.
Those with high Bronchiectasis Severity Index scores also had significantly lower alpha diversity and higher bacterial burden. Metatranscriptome sequencing showed enrichment with Streptococcus, Staphylococcus, Achromobacter, Enterobacter, Bacteroides, Porphyromonas, and Influenza A virus in the high severity group.
Targetable Pathways May Inform Future Treatment
To explore these findings further, researchers used a murine NTM infection and microaspiration model. In mice, differentially expressed genes increased over time, with more than 1,600 genes upregulated with NTM at 6 weeks and more than 2,200 with NTM plus microaspiration at 6 weeks.
The murine model showed upregulation of neutrophil extracellular traps, Th1 pathways, M1 macrophages, natural killer cells, and IFNγ at 6 weeks. Genes involved in neutrophil extracellular trap formation, tryptophan metabolism, and AKT/mTOR/HIF-1α signaling were also increased.
Together, the findings suggest that nontuberculous mycobacterial lung disease is associated with a sustained inflammatory airway environment. NET, IL-17, IL-1, and MAP kinase pathways may represent future targets for adjunctive therapies designed to support, rather than replace, antimicrobial treatment.
Reference
Singh S et al. Lower Airway Differential Gene Expression in Human and Murine Ntm+ Lung Disease Is Driven by Disease Severity/Duration and Has a Th17-Neutrophilic Signature. ATS International Conference, May 15-20, 2026.
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