Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses

Xueqi Li; Arvid Edén; Susmita Malwade; Janet L Cunningham; Jonas Bergquist; Jacob Ahlberg Weidenfors; Carl M Sellgren; Göran Engberg; Fredrik Piehl; Magnus Gisslen; Eva Kumlien; Johan Virhammar; Funda Orhan; Elham Rostami; Lilly Schwieler; Sophie Erhardt

doi:10.1016/j.bbi.2024.11.031

Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses

Brain Behav Immun. 2024 Nov 29:124:163-176. doi: 10.1016/j.bbi.2024.11.031. Online ahead of print.

Authors

Xueqi Li¹, Arvid Edén², Susmita Malwade¹, Janet L Cunningham³, Jonas Bergquist⁴, Jacob Ahlberg Weidenfors¹, Carl M Sellgren⁵, Göran Engberg⁶, Fredrik Piehl⁷, Magnus Gisslen⁸, Eva Kumlien⁹, Johan Virhammar⁹, Funda Orhan¹, Elham Rostami¹⁰, Lilly Schwieler¹, Sophie Erhardt¹¹

Affiliations

¹ Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden.
² 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.
³ Department of Medical Science, Psychiatry, Uppsala University, Uppsala 75185, Sweden; Department of Neuroscience, Karolinska Institute, Stockholm 17177, Sweden.
⁴ Analytical Chemistry and Neurochemistry, Department of Chemistry─BMC, Uppsala University, Box 599, 751 24 Uppsala, Sweden; The ME/CFS Collaborative Research Centre at Uppsala University, 751 24 Uppsala, Sweden.
⁵ Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
⁶ Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden; Institute of Sport Science and Innovations, Lithuanian Sports University, Kaunas, Lithuania.
⁷ Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm 17177, Sweden; Division of Neurology, Karolinska University Hospital, Stockholm 17176, Sweden.
⁸ 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; Public Health Agency of Sweden, Solna, Sweden.
⁹ Department of Medical Sciences, Neurology, Uppsala University, Uppsala 75185, Sweden.
¹⁰ Department of Neuroscience, Karolinska Institute, Stockholm 17177, Sweden; Department of Medical Sciences, Neurology, Uppsala University, Uppsala 75185, Sweden.
¹¹ Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden. Electronic address: sophie.erhardt@ki.se.

PMID: 39615604
DOI: 10.1016/j.bbi.2024.11.031

Abstract

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.

Keywords: Cognition; Infectious disease; Neuroinflammation.