Formerly School of Health Sciences, Cardiff Metropolitan University, Western Avenue, Cardiff CF5 2YB, Wales, U.K.
Biosci Rep. 2023 Aug 31;43(8). doi: 10.1042/BSR20230595.
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.
SARS-CoV-2（COVID-19）对色氨酸（Trp）代谢的犬尿酸（Kyn）途径（KP）产生了深刻的变化，这可能是其病理生理学的基础。KP 是产生重要细胞效应物 NAD+和调节免疫和神经元功能的中间代谢物的主要来源。Trp 代谢是受 COVID-19 影响最大的途径。16 项研究证实，病毒主要通过诱导大多数受影响组织中的吲哚胺 2,3-双加氧酶（IDO1）和肺部中的 IDO2，以及增加炎症细胞因子的释放，从而诱导 KP 激活。此外，COVID-19 还可能通过增加血浆游离 Trp 的通量和皮质醇诱导 Trp 2,3-双加氧酶（TDO）来增加 Trp 代谢。COVID-19 靶向的主要 Kyn 代谢物是犬尿酸（KA），KA 是与芳香烃受体（AhR）亲和力最大的 Kyn 代谢物，也被 COVID-19 激活。AhR 的激活引发了两个重要的系列事件：一个涉及 IDO1 诱导、KA 积累和进一步 AhR 激活的恶性循环，以及聚（ADP-核糖）聚合酶（PARP）的激活导致 NAD+耗竭和细胞死亡。病毒通过抑制其从喹啉酸合成 NAD+的主要生物合成途径，进一步剥夺宿主 NAD+，同时通过促进其从补救途径中的烟酰胺合成 NAD+。此外，PARP 的激活使 Sirtuin 1 的保护作用最小化。KP 功能障碍也可能是急性和“长 COVID”期间情绪和神经障碍的基础。需要更多研究疫苗治疗对 KP 的潜在影响，并提出涉及调节 KP 变化的治疗策略的探索。
