Nicotinamide pathways as the root cause of sepsis – an evolutionary perspective on macrophage energetic shifts

Divergent pathways of macrophage metabolism occur during infection, notably switching between oxidative phosphorylation and aerobic glycolysis (Warburg‐like metabolism). Concurrently, macrophages shift between alternate and classical activation. A key enzyme upregulated in alternatively activated macrophages is indoleamine 2,3‐dioxygenase, which converts tryptophan to kynurenine for de novo synthesis of nicotinamide. Nicotinamide can be used to replenish cellular NAD(+) supplies. We hypothesize that an insufficient cellular NAD(+) supply is the root cause of metabolic shifts in macrophages. We assert that manipulation of nicotinamide pathways may correct deleterious immune responses. We propose evaluation of nicotinamide (Vitamin B3) and analogues, including isoniazid, nicotinamide mononucleotide and nicotinamide riboside, as potential therapy for infectious causes of sepsis, including COVID‐19.