Li Xueqi, Edén Arvid, Malwade Susmita, Cunningham Janet L, Bergquist Jonas, Weidenfors Jacob Ahlberg, Sellgren Carl M, Engberg Göran, Piehl Fredrik, Gisslen Magnus, Kumlien Eva, Virhammar Johan, Orhan Funda, Rostami Elham, Schwieler Lilly, Erhardt Sophie
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden.
Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 41685, Sweden; Region Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Disease, Gothenburg, 41685, Sweden.
Brain Behav Immun. 2025 Feb;124:163-176. doi: 10.1016/j.bbi.2024.11.031. Epub 2024 Nov 29.
Long-term symptoms such as pain, fatigue, and cognitive impairments are commonly observed in individuals affected by coronavirus disease 2019 (COVID-19). Metabolites of the kynurenine pathway have been proposed to account for cognitive impairment in COVID-19 patients. Here, cerebrospinal fluid (CSF) and plasma levels of kynurenine pathway metabolites in 53 COVID-19 patients and 12 non-inflammatory neurological disease controls in Sweden were measured with an ultra-performance liquid chromatography-tandem mass spectrometry system (UPLC-MS/MS) and correlated with immunological markers and neurological markers. Single cell transcriptomic data from a previous study of 130 COVID-19 patients was used to investigate the expression of key genes in the kynurenine pathway. The present study reveals that the neuroactive kynurenine pathway metabolites quinolinic acid (QUIN) and kynurenic acid (KYNA) are increased in CSF in patients with acute COVID-19. In addition, CSF levels of kynurenine, ratio of kynurenine/tryptophan (rKT) and QUIN correlate with neurodegenerative markers. Furthermore, tryptophan is significantly decreased in plasma but not in the CSF. In addition, the kynurenine pathway is strongly activated in the plasma and correlates with the peripheral immunological marker neopterin. Single-cell transcriptomics revealed upregulated gene expressions of the rate-limiting enzyme indoleamine 2,3- dioxygenase1 (IDO1) in CD14 and CD16 monocytes that correlated with type II-interferon response exclusively in COVID-19 patients. In summary, our study confirms significant activation of the peripheral kynurenine pathway in patients with acute COVID-19 and, notably, this is the first study to identify elevated levels of kynurenine metabolites in the central nervous system associated with the disease. Our findings suggest that peripheral inflammation, potentially linked to overexpression of IDO1 in monocytes, activates the kynurenine pathway. Increased plasma kynurenine, crossing the blood-brain barrier, serves as a source for elevated brain KYNA and neurotoxic QUIN. We conclude that blocking peripheral-to-central kynurenine transport could be a promising strategy to protect against neurotoxic effects of QUIN in COVID-19 patients.
长期症状，如疼痛、疲劳和认知障碍，在感染2019冠状病毒病（COVID-19）的个体中很常见。犬尿氨酸途径的代谢产物被认为是导致COVID-19患者认知障碍的原因。在此，使用超高效液相色谱-串联质谱系统（UPLC-MS/MS）测量了瑞典53名COVID-19患者和12名非炎性神经疾病对照者脑脊液（CSF）和血浆中犬尿氨酸途径代谢产物的水平，并将其与免疫标志物和神经标志物进行关联。来自先前对130名COVID-19患者研究的单细胞转录组数据用于研究犬尿氨酸途径中关键基因的表达。本研究表明，急性COVID-19患者脑脊液中具有神经活性的犬尿氨酸途径代谢产物喹啉酸（QUIN）和犬尿酸（KYNA）增加。此外，脑脊液中犬尿氨酸水平、犬尿氨酸/色氨酸比值（rKT）和QUIN与神经退行性标志物相关。此外，血浆中色氨酸显著降低，但脑脊液中未降低。此外血浆中犬尿氨酸途径被强烈激活，并与外周免疫标志物新蝶呤相关。单细胞转录组学显示，COVID-19患者中CD14和CD16单核细胞中限速酶吲哚胺2,3-双加氧酶1（IDO1）的基因表达上调，且仅与II型干扰素反应相关。总之，我们的研究证实急性COVID-19患者外周犬尿氨酸途径显著激活，值得注意的是这是第一项确定与该疾病相关的中枢神经系统中犬尿氨酸代谢产物水平升高的研究。我们的研究结果表明，外周炎症可能与单核细胞中IDO1的过表达有关，激活了犬尿氨酸途径。血浆中犬尿氨酸增加，穿过血脑屏障，成为脑内KYNA和神经毒性QUIN升高的来源。我们得出结论，阻断外周至中枢的犬尿氨酸转运可能是预防COVID-19患者中QUIN神经毒性作用的一种有前景的策略。
