Fig. 7: NAD(H) homeostasis protects the host in TB.

Summary graphic depicting the proposed model for the metabolism of macrophages responding to stimulation with IFNγ, how Mtb disrupts this response, and how NAM restores it. A Following stimulation with IFNγ, macrophages exhibit high rates of glycolysis and lactate metabolism, necessitating the rapid cycling between NAD⁺ and NADH. Under these conditions, the NAD⁺ salvage pathway effectively maintains the pool of NAD(H). Together, this metabolic response enables the functional activation of the macrophage by IFNγ. B In Mtb-infected macrophages, the metabolic response to IFNγ is prevented by disrupting NAD(H) homeostasis. This may be due to decreased synthesis or increased NAD+ consumption. Regardless, reduced NAD(H) availability impairs the conversion of pyruvate to lactate, leading to an accumulation of pyruvate. Pyruvate is then converted to citrate which inhibits glycolytic flux. The functional consequence is an impairment in the host-protective effects of IFNγ. C Following treatment with NAM, Mtb-infected macrophages can respond effectively to IFNγ, as the NAM is metabolized to NAD⁺. While the insult to NAD(H) homeostasis is likely still present, NAM supplementation addresses the immediate downstream impact of this insult by supporting NAD⁺ synthesis. Consequently, the metabolic and functional responses to IFNγ and other environmental signals is restored, ultimately leading to host protection in TB.