Targeting the kynurenine pathway in viral infections: neuropsychiatric implications, in vitro drug testing and target validation

Viral infections frequently induce persistent cognitive and neuropsychiatric sequelae, potentially mediated through immune-driven dysregulation of tryptophan metabolism along the kynurenine pathway. This pathway generates neuroactive metabolites like kynurenic acid (KYNA) and quinolinic acid (QUIN), which are implicated in psychosis and cognitive deficit. While kynurenine aminotransferase (KAT) II has been proposed as a therapeutic target, its applicability in inflammatory context remains unclear.

This thesis investigates the role of the kynurenine pathway in viral-induced neuropsychiatric impairment and explores therapeutic strategies through four integrated studies. Using a combination of clinical, experimental and computational approaches, we:

1. Characterized kynurenine pathway dysregulation in Coronavirus Disease 2019 (COVID-19) (Paper I) and tick-borne encephalitis (TBE) patients (Paper II), employing ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to quantify kynurenine pathway metabolites in cerebrospinal fluid (CSF) and serum/plasma.

2. Identified correlations between elevated CSF levels of QUIN and kynurenine and neurodegenerative markers in acute COVID-19 (Paper I) and demonstrated persistent peripheral-central pathway dysregulation in TBE linked to long-term attention/vigilance deficits (Paper II).

3. Developed human-derived in vitro models (primary fibroblasts, monocytes, A-431 carcinoma cells) to study cytokine-driven kynurenine metabolism (Paper III), revealing KAT III's critical role in inflammation-associated KYNA production.

4. Validated KAT III as a novel therapeutic target using pharmacological inhibition in immune-activated systems and postmortem brain tissue from neuroinflammatory conditions (Paper IV).

Key findings include:

• Peripheral inflammation drives central kynurenine metabolite accumulation via monocyte indoleamine 2,3-dioxygenase 1 (IDO1) upregulation in COVID-19.
• Serum kynurenine/tryptophan ratios (rKT) predict long-term cognitive impairment in TBE.
• KAT III (rather than KAT II) emerges as the dominant enzymatic contributor to neuroactive metabolite shifts during immune activation.

In conclusion, these results establish the kynurenine pathway as both a biomarker source and mechanistic bridge between viral-induced inflammation and cognitive sequelae. Our data strongly suggest KAT III inhibition as a promising strategy for mitigating neuropsychiatric complications, and we further provide validated models for high-throughput therapeutic screening. By integrating clinical observations with mechanistic studies, this thesis lays a foundation for targeted interventions in infection-associated neurological disorders.

List of scientific papers

I. Xueqi Li, Arvid Eden, Susmita Malwade, Janet L. Cunningham, Jacob Ahlberg Weidenfors, Carl M. Sellgren, Göran Engberg, Fredrik Piehl, Magnus Gisslen, Eva Kumlien, Johan Virhammar, Funda Orhan, Elham Rostami, Lilly Schwieler, Sophie Erhardt. "Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses." Brain, Behavior, and Immunity 124 (2025): 163-176. https://doi.org/10.1016/j.bbi.2024.11.031

II. Jacob Ahlberg Weidenfors, Vytautas Griška, Xueqi Li, Aistė Pranckevičienė, Jolita Pakalnienė, Ann Atlas, Elisabeth Franzén-Röhl, Fredrik Piehl, Lars Lindquist, Auksė Mickienė, Göran Engberg, Lilly Schwieler, Sophie Erhardt. "Dysregulation of the kynurenine pathway is related to persistent cognitive impairment in tick-borne encephalitis." Brain, Behavior, and Immunity 125 (2025): 452-465. https://doi.org/10.1016/j.bbi.2025.02.005

III. Xueqi Li, Anthi Faka, Marta Gómez-Galán, Neda Khanlarkhani, Göran Engberg, Sophie Imbeault, Carl Sellgren, Simon Cervenka, Nikolaos Venizelos, Lilly Schwieler, Funda Orhan, Sophie Erhardt. "Synergistic Effects of IFN-y and IL-1B on Kynurenine Pathway Activation and the Role of KAT Isoforms in KYNA Synthesis in Human Primary Fibroblasts." [Manuscript]

IV. Varvara Louvrou, Lilly Schwieler, Xueqi Li, Xi-Cong Liu, Anthi Faka, Annika Lindqvist, Ylva Gravenfors, Funda Orhan, Susmita Malwade, Carl Sellgren, Marta Gomez Gallan, Federico Picciau, Sophie Imbeault, Robert Schwarcz, Sophie Erhardt. "KAT Ill as the Key Enzyme Driving Immune-Induced Kynurenic Acid Synthesis: A Novel Target for cognitive dysfuntions and psychotic disorders." [Manuscript]