M. avium pulmonary disease inversely correlates with macaque lung commensal Tropheryma
Description
Rationale: Nontuberculous mycobacteria (NTM) pulmonary disease (NTMPD) cases are rapidly increasing primarily in individuals over the age of 65 and have exceeded that of Mycobacterium tuberculosis (M. tb). While the causes for increased disease severity in immunocompromised NTM cases are well understood, the host factors leading to higher severity in immunocompetent older patients remain elusive. Objectives: To address this knowledge gap, we leveraged a rhesus macaque model of NTMPD where young and aged animals are inoculated intrabronchially with M. avium subsp. hominissuis (MAH) to assess the role of the lung microbial community and immune response of young and aged in modulating disease severity. Methods: Animals were infected in the right upper, middle, and caudal lobes. Disease progression, bacterial load, microbial community compositions, and immunological changes were monitored longitudinally using computed tomography, cultures, 16S amplicon sequencing, histology, and flow cytometry, as well as single cell and spatial transcriptomic analyses. Measurements and Main Results: Although bacterial load and clearance were comparable between the young and aged animals, CT scans indicate worse radiological outcomes in older animals. Aged animals mounted an inflammatory response that favored acute phase over a Th1 response and scRNA sequencing indicate persistent inflammatory signature in aged animals. Finally, microbial community analysis revealed significant dysbiosis in the right lung and an inverse correlation between the abundance of an uncultured Tropheryma and MAHPD severity as assessed by radiographic changes. Conclusions: Collectively, these data reveal that hyperinflammation and loss of Tropheryma contribute to MAHPD severity in aging macaques.
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Institutions
- University of KentuckyKY, Lexington