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Author ORCID Identifier
https://orcid.org/0009-0008-7461-0844
Date Available
4-10-2026
Year of Publication
2026
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Microbiology, Immunology, and Molecular Genetics
Faculty
Ilhem Messaoudi
Faculty
Brian Higgins
Abstract
Aging is associated with dysregulated immunity and increased susceptibility to infection, a phenomenon dubbed as immunosenescence and characterized by reduced naïve T and B cell pools, altered innate immune function, and chronic low-grade inflammation. Nontuberculous mycobacterial (NTM) pulmonary disease (NTMPD) is an increasingly relevant chronic lung infection that disproportionately affects older adults (65+ years) and immunocompromised individuals. However, the host factors underlying increased disease severity in aged patients remain poorly defined. Literature suggests that effective control of NTM relies on coordinated innate and adaptive immune responses, particularly macrophage activation and Th1 cytokine signaling. Using a rhesus macaque model that closely recapitulates human NTMPD, we demonstrate that aged animals develop more severe and persistent pulmonary disease following infection with Mycobacterium avium subsp. hominissuis (MAH). This increased disease severity is accompanied by dysregulated immune responses, including diminished Th1-associated cytokine levels such as IFNγ and TNFα, prolonged elevation of the acute-phase IL-6 inflammatory mediator, and aberrant macrophage activation. Furthermore, we employed Visium spatial transcriptomics to investigate the differences between lung tissue from young and aged macaques. We found that the poor outcome in aged animals may arise due to the chronic inflammatory signatures observed across several immune and structural lung cells in aged tissue as well as impaired tissue repair signaling. The age-associated loss of the macaque lung commensal Tropheryma could also contribute to poor outcomes. Indeed, animals treated with nebulized antibiotics to induce lung dysbiosis or a TNF blocking agent prior to infection with MAH exhibited increased immune dysregulation and susceptibility to cavitary and granulomatous disease, respectively. Collectively, these data provide the field with a robust preclinical nonhuman primate model that recapitulates human NTMPD, which would facilitate the development and testing of novel therapeutics against NTM.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2026.34
Archival?
Archival
Funding Information
These studies were supported by the National Institute of Allergy and Infectious Diseases (5 R01AA028735-06; Mechanisms of increased susceptibility to pulmonary Nontuberculous Mycobacterial disease in the elderly) from 2021 to 2025 and by the National Institute on Alcohol Abuse and Alcoholism (5 T32AA027488-07; Interdisciplinary Training in Alcohol Research) from 2023 to 2025.
Recommended Citation
Napier, Ethan G., "THE RHESUS MACAQUE MODEL OF MYCOBACTERIUM AVIUM INFECTION REVEALS THAT AGE-RELATED DISEASE IS DUE IN PART TO CHRONIC INFLAMMATION AND LUNG MICROBIAL DYSBIOSIS" (2026). Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics. 34.
https://uknowledge.uky.edu/microbio_etds/34
