The kynurenine pathway of tryptophan metabolism: a neglected therapeutic target of COVID-19 pathophysiology and immunotherapy.

SARS-CoV-2 (COVID-19) exerts profound changes in the kynurenine (Kyn) pathway (KP) of tryptophan (Trp) metabolism that may underpin its pathophysiology. The KP is the main source of the vital cellular effector NAD+ and intermediate metabolites that modulate immune and neuronal functions. Trp metabolism is the top pathway influenced by COVID-19. Sixteen studies established virus-induced activation of the KP mediated mainly by induction of indoleamine 2,3-dioxygenase (IDO1) in most affected tissues and of IDO2 in lung by the increased release of proinflammatory cytokines but could additionally involve increased flux of plasma free Trp and induction of Trp 2,3-dioxygenase (TDO) by cortisol. The major Kyn metabolite targeted by COVID-19 is kynurenic acid (KA), the Kyn metabolite with the greatest affinity for the aryl hydrocarbon receptor (AhR), which is also activated by COVID-19. AhR activation initiates two important series of events: a vicious circle involving IDO1 induction, KA accumulation and further AhR activation, and activation of poly (ADP-ribose) polymerase (PARP) leading to NAD+ depletion and cell death. The virus further deprives the host of NAD+ by inhibiting its main biosynthetic pathway from quinolinic acid, while simultaneously acquiring NAD+ by promoting its synthesis from nicotinamide in the salvage pathway. Additionally, the protective effects of sirtuin 1 are minimised by the PARP activation. KP dysfunction may also underpin the mood and neurological disorders acutely and during 'long COVID'. More studies of potential effects of vaccination therapy on the KP are required and exploration of therapeutic strategies involving modulation of the KP changes are proposed.