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

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 () and Adrie J. C. Steyn ()
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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
Joel N. Glasgow: University of Alabama at Birmingham
Anupam Agarwal: University of Alabama at Birmingham
Adrie J. C. Steyn: University of Alabama at Birmingham

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40545-x

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