Frontiers in Immunology (Jan 2023)
Human alveolar macrophage metabolism is compromised during Mycobacterium tuberculosis infection
- Laura E. Mendonca,
- Laura E. Mendonca,
- Erwan Pernet,
- Erwan Pernet,
- Nargis Khan,
- Nargis Khan,
- Joaquin Sanz,
- Eva Kaufmann,
- Eva Kaufmann,
- Jeffrey Downey,
- Jeffrey Downey,
- Alexandre Grant,
- Alexandre Grant,
- Marianna Orlova,
- Marianna Orlova,
- Erwin Schurr,
- Erwin Schurr,
- Connie Krawczyk,
- Connie Krawczyk,
- Russell G. Jones,
- Russell G. Jones,
- Luis B. Barreiro,
- Luis B. Barreiro,
- Luis B. Barreiro,
- Maziar Divangahi,
- Maziar Divangahi
Affiliations
- Laura E. Mendonca
- The Research Institute of the McGill University Health Centre, Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology and
- Laura E. Mendonca
- McGill International TB Centre, Montreal, QC, Canada
- Erwan Pernet
- The Research Institute of the McGill University Health Centre, Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology and
- Erwan Pernet
- McGill International TB Centre, Montreal, QC, Canada
- Nargis Khan
- The Research Institute of the McGill University Health Centre, Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology and
- Nargis Khan
- McGill International TB Centre, Montreal, QC, Canada
- Joaquin Sanz
- Institute for Biocomputation and Physics of Complex Systems (BIFI) for Biocomputation and Physics of Complex Systems and Department of Theoretical Physics, University of Zaragoza, Zaragoza, Spain
- Eva Kaufmann
- The Research Institute of the McGill University Health Centre, Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology and
- Eva Kaufmann
- McGill International TB Centre, Montreal, QC, Canada
- Jeffrey Downey
- The Research Institute of the McGill University Health Centre, Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology and
- Jeffrey Downey
- McGill International TB Centre, Montreal, QC, Canada
- Alexandre Grant
- The Research Institute of the McGill University Health Centre, Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology and
- Alexandre Grant
- McGill International TB Centre, Montreal, QC, Canada
- Marianna Orlova
- McGill International TB Centre, Montreal, QC, Canada
- Marianna Orlova
- Department of Medicine and Human Genetics, McGill University. Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Erwin Schurr
- McGill International TB Centre, Montreal, QC, Canada
- Erwin Schurr
- Department of Medicine and Human Genetics, McGill University. Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Connie Krawczyk
- Department of Physiology, Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
- Connie Krawczyk
- VanAndel Institute, Center for Cancer and Cell Biology, Grand Rapids, MI, United States
- Russell G. Jones
- Department of Physiology, Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
- Russell G. Jones
- VanAndel Institute, Center for Cancer and Cell Biology, Grand Rapids, MI, United States
- Luis B. Barreiro
- McGill International TB Centre, Montreal, QC, Canada
- Luis B. Barreiro
- Department of Genetics, Centre hospitalier de l'Université (CHU) Sainte-Justine Research Center, Montreal, QC, Canada
- Luis B. Barreiro
- University of Chicago, Department of Medicine, Section of Genetic Medicine, Chicago, IL, United States
- Maziar Divangahi
- The Research Institute of the McGill University Health Centre, Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology and
- Maziar Divangahi
- McGill International TB Centre, Montreal, QC, Canada
- DOI
- https://doi.org/10.3389/fimmu.2022.1044592
- Journal volume & issue
-
Vol. 13
Abstract
Pulmonary macrophages have two distinct ontogenies: long-lived embryonically-seeded alveolar macrophages (AM) and bone marrow-derived macrophages (BMDM). Here, we show that after infection with a virulent strain of Mycobacterium tuberculosis (H37Rv), primary murine AM exhibit a unique transcriptomic signature characterized by metabolic reprogramming distinct from conventional BMDM. In contrast to BMDM, AM failed to shift from oxidative phosphorylation (OXPHOS) to glycolysis and consequently were unable to control infection with an avirulent strain (H37Ra). Importantly, healthy human AM infected with H37Ra equally demonstrated diminished energetics, recapitulating our observation in the murine model system. However, the results from seahorse showed that the shift towards glycolysis in both AM and BMDM was inhibited by H37Rv. We further demonstrated that pharmacological (e.g. metformin or the iron chelator desferrioxamine) reprogramming of AM towards glycolysis reduced necrosis and enhanced AM capacity to control H37Rv growth. Together, our results indicate that the unique bioenergetics of AM renders these cells a perfect target for Mtb survival and that metabolic reprogramming may be a viable host targeted therapy against TB.
Keywords
- tuberculosis
- immunometabolism
- immunity
- pulmonary macrophages
- metabolic reprograming
- cell death programs
