Immunological and microbial shifts in the aging rhesus macaque lung during nontuberculous mycobacterial infection

作者：Isaac R. Cinco, Ethan G. Napier, Nicholas S. Rhoades, Michael H. Davies, Derek B. Allison, Steven G. Kohama, Luiz E. Bermudez, Kevin Winthrop, Cristina Fuss, Eliot R. Spindel, Ilhem Messaoudi · 发表于：mBio · 年份：2024 · DOI：10.1128/mbio.00829-24 · 被引用次数：11 · 研究领域：Mycobacterium research and diagnosis、Tuberculosis Research and Epidemiology、Immune Cell Function and Interaction

ABSTRACT Nontuberculous mycobacteria (NTM) are environmentally ubiquitous organisms that predominately cause NTM pulmonary disease (NTMPD) in individuals over the age of 65. The incidence of NTMPD has increased in the U.S., exceeding that of Mycobacterium tuberculosis . However, the mechanisms leading to higher susceptibility and severity of NTMPD with aging are poorly defined in part due to the lack of animal models that accurately recapitulate human disease. Here, we compared bacterial load, microbial communities, and host responses longitudinally between three young (two female and one male) and two aged (two female) rhesus macaques inoculated with Mycobacterium avium subsp. hominissuis (MAH) in the right caudal lobe. Unilateral infection resulted in a low bacterial load in both young and aged animals confined to the infected side. Although a robust inflammatory response was only observed in the inoculated lung, immune cell infiltration and antigen-specific T cells were detected in both lungs. Computed tomography, gross pathology, and histopathology revealed increased disease severity and persistence of bacterial DNA in aged animals. Additional analyses showed the translocation of gut and oral-pharyngeal bacterial DNA into the lower respiratory microbiome. Finally, single-cell RNA sequencing revealed a heightened inflammatory response to MAH infection by alveolar macrophages in aged animals. These data are consistent with the model that increased disease severity in the ag...