NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis
Abstract Mycobacterium tuberculosis (Mtb) disrupts glycolytic flux in infected myeloid cells through an unclear mechanism. Flux through the glycolytic pathway in myeloid cells is inextricably linked to the availability of NAD+, which is maintained by NAD+ salvage and lactate metabolism. Using lung t...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40545-x |
| _version_ | 1797558144201654272 |
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| author | Hayden T. Pacl Krishna C. Chinta Vineel P. Reddy Sajid Nadeem Ritesh R. Sevalkar Kievershen Nargan Kapongo Lumamba Threnesan Naidoo Joel N. Glasgow Anupam Agarwal Adrie J. C. Steyn |
| author_facet | Hayden T. Pacl Krishna C. Chinta Vineel P. Reddy Sajid Nadeem Ritesh R. Sevalkar Kievershen Nargan Kapongo Lumamba Threnesan Naidoo Joel N. Glasgow Anupam Agarwal Adrie J. C. Steyn |
| author_sort | Hayden T. Pacl |
| collection | DOAJ |
| description | Abstract Mycobacterium tuberculosis (Mtb) disrupts glycolytic flux in infected myeloid cells through an unclear mechanism. Flux through the glycolytic pathway in myeloid cells is inextricably linked to the availability of NAD+, which is maintained by NAD+ salvage and lactate metabolism. Using lung tissue from tuberculosis (TB) patients and myeloid deficient LDHA (Ldha LysM−/− ) mice, we demonstrate that glycolysis in myeloid cells is essential for protective immunity in TB. Glycolytic myeloid cells are essential for the early recruitment of multiple classes of immune cells and IFNγ-mediated protection. We identify NAD+ depletion as central to the glycolytic inhibition caused by Mtb. Lastly, we show that the NAD+ precursor nicotinamide exerts a host-dependent, antimycobacterial effect, and that nicotinamide prophylaxis and treatment reduce Mtb lung burden in mice. These findings provide insight into how Mtb alters host metabolism through perturbation of NAD(H) homeostasis and reprogramming of glycolysis, highlighting this pathway as a potential therapeutic target. |
| first_indexed | 2024-03-10T17:26:18Z |
| format | Article |
| id | doaj.art-4e4ad46f3eb246c2ab7a16acbf265d77 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:26:18Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-4e4ad46f3eb246c2ab7a16acbf265d772023-11-20T10:09:10ZengNature PortfolioNature Communications2041-17232023-09-0114111810.1038/s41467-023-40545-xNAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosisHayden T. Pacl0Krishna C. Chinta1Vineel P. Reddy2Sajid Nadeem3Ritesh R. Sevalkar4Kievershen Nargan5Kapongo Lumamba6Threnesan Naidoo7Joel N. Glasgow8Anupam Agarwal9Adrie J. C. Steyn10Department of Microbiology, University of Alabama at BirminghamDepartment of Microbiology, University of Alabama at BirminghamDepartment of Microbiology, University of Alabama at BirminghamDepartment of Microbiology, University of Alabama at BirminghamDepartment of Microbiology, University of Alabama at BirminghamAfrica Health Research Institute, University of KwaZulu NatalAfrica Health Research Institute, University of KwaZulu NatalAfrica Health Research Institute, University of KwaZulu NatalDepartment of Microbiology, University of Alabama at BirminghamDepartment of Medicine, Division of Nephrology, Nephrology Research and Training Center, University of Alabama at BirminghamDepartment of Microbiology, University of Alabama at BirminghamAbstract Mycobacterium tuberculosis (Mtb) disrupts glycolytic flux in infected myeloid cells through an unclear mechanism. Flux through the glycolytic pathway in myeloid cells is inextricably linked to the availability of NAD+, which is maintained by NAD+ salvage and lactate metabolism. Using lung tissue from tuberculosis (TB) patients and myeloid deficient LDHA (Ldha LysM−/− ) mice, we demonstrate that glycolysis in myeloid cells is essential for protective immunity in TB. Glycolytic myeloid cells are essential for the early recruitment of multiple classes of immune cells and IFNγ-mediated protection. We identify NAD+ depletion as central to the glycolytic inhibition caused by Mtb. Lastly, we show that the NAD+ precursor nicotinamide exerts a host-dependent, antimycobacterial effect, and that nicotinamide prophylaxis and treatment reduce Mtb lung burden in mice. These findings provide insight into how Mtb alters host metabolism through perturbation of NAD(H) homeostasis and reprogramming of glycolysis, highlighting this pathway as a potential therapeutic target.https://doi.org/10.1038/s41467-023-40545-x |
| spellingShingle | Hayden T. Pacl Krishna C. Chinta Vineel P. Reddy Sajid Nadeem Ritesh R. Sevalkar Kievershen Nargan Kapongo Lumamba Threnesan Naidoo Joel N. Glasgow Anupam Agarwal Adrie J. C. Steyn NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis Nature Communications |
| title | NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis |
| title_full | NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis |
| title_fullStr | NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis |
| title_full_unstemmed | NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis |
| title_short | NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis |
| title_sort | nad h homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis |
| url | https://doi.org/10.1038/s41467-023-40545-x |
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