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NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis

Author

Listed:
  • Hayden T. Pacl

    (University of Alabama at Birmingham)

  • Krishna C. Chinta

    (University of Alabama at Birmingham)

  • Vineel P. Reddy

    (University of Alabama at Birmingham)

  • Sajid Nadeem

    (University of Alabama at Birmingham)

  • Ritesh R. Sevalkar

    (University of Alabama at Birmingham)

  • Kievershen Nargan

    (University of KwaZulu Natal)

  • Kapongo Lumamba

    (University of KwaZulu Natal)

  • Threnesan Naidoo

    (University of KwaZulu Natal
    Walter Sisulu University)

  • Joel N. Glasgow

    (University of Alabama at Birmingham)

  • Anupam Agarwal

    (University of Alabama at Birmingham)

  • Adrie J. C. Steyn

    (University of Alabama at Birmingham
    University of KwaZulu Natal
    University of Alabama at Birmingham)

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 (LdhaLysM−/−) 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.

Suggested Citation

  • 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, 2023. "NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40545-x
    DOI: 10.1038/s41467-023-40545-x
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    References listed on IDEAS

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    1. Erika M. Palmieri & Marieli Gonzalez-Cotto & Walter A. Baseler & Luke C. Davies & Bart Ghesquière & Nunziata Maio & Christopher M. Rice & Tracey A. Rouault & Teresa Cassel & Richard M. Higashi & Andre, 2020. "Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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