Characterizing and correcting immune dysfunction in non-tuberculous mycobacterial disease

Ratnatunga, Champa N., Tungatt, Katie, Proietti, Carla, Halstrom, Sam, Holt, Michael R., Lutzky, Viviana P., Price, Patricia, Doolan, Denise L., Bell, Scott C., Field, Matt A., Kupz, Andreas, Thomson, Rachel M., and Miles, John J. (2022) Characterizing and correcting immune dysfunction in non-tuberculous mycobacterial disease. Frontiers in Immunology, 13. 1047781.

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Abstract

Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is a chronic, progressive, and growing worldwide health burden associated with mounting morbidity, mortality, and economic costs. Improvements in NTM-PD management are urgently needed, which requires a better understanding of fundamental immunopathology. Here, we examine temporal dynamics of the immune compartment during NTM-PD caused by Mycobacterium avium complex (MAC) and Mycobactereoides abscessus complex (MABS). We show that active MAC infection is characterized by elevated T cell immunoglobulin and mucin-domain containing-3 expression across multiple T cell subsets. In contrast, active MABS infection was characterized by increased expression of cytotoxic T-lymphocyte-associated protein 4. Patients who failed therapy closely mirrored the healthy individual immune phenotype, with circulating immune network appearing to 'ignore' infection in the lung. Interestingly, immune biosignatures were identified that could inform disease stage and infecting species with high accuracy. Additionally, programmed cell death protein 1 blockade rescued antigen-specific IFN-gamma secretion in all disease stages except persistent infection, suggesting the potential to redeploy checkpoint blockade inhibitors for NTM-PD. Collectively, our results provide new insight into species-specific 'immune chatter' occurring during NTM-PD and provide new targets, processes and pathways for diagnostics, prognostics, and treatments needed for this emerging and difficult to treat disease.

Item ID: 77062
Item Type: Article (Research - C1)
ISSN: 1664-3224
Keywords: non-tuberculous mycobacteria, mycobacterial immunity, immune cell dysfunction, high-dimensional immunoprofiling, immune modulation
Copyright Information: Copyright © 2022 Ratnatunga, Tungatt, Proietti, Halstrom, Holt, Lutzky, Price, Doolan, Bell, Field, Kupz, Thomson and Miles. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Funders: National Health and Medical Research Council (NHMRC)
Projects and Grants: NHMRC Career Development Level 1 Fellowship 1031652, NHMRC Career Development 2 Fellowship 1131732, NHMRC Principal Research Fellowship 1137285, NHMRC CJ Martin Fellowship 5121190, NHMRC Career Development Fellowship 1140709
Date Deposited: 14 Dec 2022 08:40
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3207 Medical microbiology > 320701 Medical bacteriology @ 100%
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