NAD(H) homeostasis is essential for host protection mediated by glycolytic myeloid cells in tuberculosis

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 the protective effects of IFNγ. We identified NAD⁺ depletion as central to the glycolytic inhibition caused by Mtb. Lastly, we show that the NAD⁺ precursor nicotinamide exerts a host-directed, antimycobacterial effect, and that nicotinamide prophylaxis and treatment reduces Mtb lung burden in vivo. These findings provide new 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.