Impact of aging on the immunological and microbial landscape of the lung during non-tuberculous mycobacterial infection

Nontuberculous mycobacteria (NTM) are environmentally ubiquitous and predominately cause pulmonary disease (NTMPD). The incidence of NTMPD has steadily increased and is now more prevalent than that of Mycobacterium tuberculosis (M. tb) in the US. Moreover, the prevalence of NTMPD increases with age; therefore, it is likely that the burden of NTMPD will continue to increase in the coming decades as the number of those over the age of 65 increased in the U.S population. However, the mechanisms leading to higher susceptibility and severity of NTMPD with aging are poorly defined. Here, we used a rhesus macaque model of intrabronchial infection with M. avium complex in young and aged animals to address this knowledge gap. Unilateral infection resulted in a robust inflammatory response predominantly in the inoculated lung, however, immune cell infiltration and antigen-specific T cell responses were detected in both lungs. Nasal, oral, and fecal swabs, and BAL samples were profiled using 16S amplicon sequencing. These data suggested that decompartmentalization of the lower respiratory microbiome was occurring, evidenced by detection of bacterial DNA typically found in the gut and oral-pharyngeal cavity in bronchoalveolar samples following infection. Radiographic studies, gross pathology, and histopathology examination revealed increased disease severity in aged compared to young animals with pulmonary consolidation, edema, and lesions. Finally, single cell RNA sequencing indicated that aged animals generated a dysregulated macrophage and CD8 T cell response to MAC infection.