Age-related severity of nontuberculous mycobacterial lung disease is mediated by aberrant macrophage responses and lung microbial dysbiosis.

OBJECTIVES

Although cases of nontuberculous mycobacteria (NTM) pulmonary disease (NTMPD) are rapidly increasing primarily in individuals over the age of 65, the host factors leading to higher occurrence in immunocompetent older patients remain elusive. This study aims to elucidate host factors leading to higher nontuberculous mycobacterial pulmonary disease occurrence in older immunocompetent patients.

METHODS

To address these challenges, we used a rhesus macaque model developed by our laboratory where macaques were infected via intrabronchial inoculation with M. avium subsp. hominissuis (MAH). Disease progression, bacterial load, microbial community compositions, and host responses were monitored longitudinally using computed tomography, culturing, 16S amplicon sequencing, histology, flow cytometry, and single cell RNA sequencing.

RESULTS

Despite comparable kinetics of bacterial clearance, computed tomography scans indicated more severe radiological outcomes in older animals which mounted predominantly an inflammatory acute phase response rather than a Th1 response. Single cell RNA sequencing indicated a persistent inflammatory signature in aged animals. Microbial community analysis revealed an age-mediated loss of an uncultured Tropheryma species that was inversely correlated with severity of radiographic changes.

CONCLUSIONS

These data reveal that nontuberculous mycobacterial pulmonary disease severity in the aged animals is driven by dysregulated inflammatory responses and dysbiosis of the lung microbiome.