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Present review focuses on the possible role of tryptophan (Trp) – kynurenine (Kyn) pathway in the mechanism(s) of COVID-19 associated psychiatric complications. SARS-CoV-2 infection, that causes COVID-19, triggers overproduction of interferon-gamma (IFNG), a pro-inflammatory cytokine. IFNG activates indoleamine 2,3-dioxygenase-1 (IDO), enzyme that catalyzes Trp conversion into Kyn, and enzymes of down-stream Kyn pathway that catalyze Kyn conversion into 3-hydroxykynurenine, kynurenic and anthranilic acids in brain and peripheral organs. We reviewed data on SARS-CoV-2 - IFNG – induced changes of peripheral Trp – Kyn pathway, considering their translational potential for personalized psychiatric care. Elevated blood levels of Trp – Kyn pathway metabolites were correlated with the severity of symptoms and predicted the negative outcomes in COVID-19 patients. Association of Trp – Kyn pathway up-regulation with psychiatric complication in non-COVID-19 patients suggests that activation of these pathways contribute to the mechanism(s) of COVID-19 associated psychiatric conditions as well. Increased risk of psychiatric complications in carriers of T (high producer) allele of polymorphic IFNG gene and elevation of serum levels of Kyn and its metabolites in interferon-alpha treated hepatitis C virus patients provides further support for such a suggestion. Assessment of blood levels of Kyn and its metabolites, and polymorphism of Trp – Kyn pathway genes might be developed into personalized biological markers predicting gender/aging dependent individual’s risk of psychiatric complications in COVID-19 patients. Up-regulation of IFNG and IDO is necessary for anti-viral protection. Therefore, inhibition of down-stream Kyn pathway should be considered as a new target for prevention/treatment of COVID-19 and COVID-19-associated psychiatric complications.
Varatharaj A, Thomas N, Ellul MA, Davies, N.W.S., et al. (2020 June 25). Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry. S2215-0366(20)30287-X. doi: 10.1016/S2215-0366(20)30287-X.
], and association of IFNG-inducible up-regulation of Trp – Kyn pathway with psychiatric conditions in non-COVID-19. While IFNG stimulates Trp – Kyn pathway in microglia, specifically affected by SARS-CoV-2 [
] and peripheral organs, current review focuses on SAR – IFNG – induced changes of peripheral (e,g, plasma, serum) changes of Trp – Kyn pathway considering their translational potential for personalized psychiatric care.
Tryptophan – Kynurenine pathway
Tryptophan conversion into kynurenine
Tryptophan (Trp) is an essential (for humans) amino acid. About 3–5% of Trp is metabolized into serotonin (along methoxyindole pathway), while about 95% of non-protein Trp is metabolized along kynurenine (Kyn) pathway resulting in biosynthesis of NAD+, an ubiquitarian coenzyme involved in basic cellular processes [
] (Fig. 1). Formation of Kyn from Trp is catalyzed either by Trp-2,3-dioxygenase 2 (TDO) or by indoleamine 2,3-dioxygenase I (IDO) and 2. IDO, in difference with liver TDO, is present in most mammalian organs, including brain, lungs, blood mononuclear phagocytes, intestine, placenta, adipocytes. [
]. TDO is activated by stress hormones (e.g., cortisol) and substrate (Trp) while IDO is transcriptionally induced by pro-inflammatory cytokines, e.g., interferon-gamma (IFNG) [
One of the consequences of IFNG – induced IDO activation is an increased availability of Kyn as a substrate for production of Kyn down-stream derivatives: 3-hydroxykynurenine (3HK), catalyzed by kynurenine 3-monooxygenase (KMO); kynurenic acid (KYNA), catalyzed by kynurenine aminotransferases (KAT), and anthranilic acid (AA), catalyzed by kynureninase 1(kynase). Under physiological conditions KMO affinity to Kyn (Km 25 µM) is higher than that of Kynase (Km 250 µM) favoring conversion of Kyn into 3HK rather than into AA [
3HK is further catalyzed by kynase 2 into 3-hydroxyanthranilic acid, an immediate precursor of neurotoxic quinolinic acid (QUIN), an agonist to NMDA receptors (NMDAR) [
Baranyi A, Meinitzer A, Breitenecker RJ, Amouzadeh-Ghadikolai O, et al Quinolinic Acid Responses during Interferon-alpha-Induced Depressive Symptomatology in Patients with Chronic Hepatitis C Infection - A Novel Aspect for Depression and Inflammatory Hypothesis. PLoS One 2015;10(9):e0137022. doi: 10.1371/journal.pone.0137022. eCollection 2015.PMID: 26368809.
KAT, in addition to formation of KYNA from Kyn, catalyzes conversion of 3HK into xanthurenic acid (XA), an 8-hydroxylated analog of KYNA, an agonist to mGlu2/3 metabotropic glutamate receptors [
SARS-CoV-2 infection and kynurenine formation from tryptophan
Considering that SARS-CoV-2 infection triggers production of IFNG, a pro-inflammatory cytokine, that activates IDO, up-regulation of Kyn formation from Trp could be expected in SARS-CoV-2 infection. Notably, prospective study revealed a 1.3-fold increase in serum levels of cortisol (p = 0.006) and 1.5-fold increase of Kyn and decreased Trp levels in severe cases and COVID-19 who died [
Roberts I, Muelas MW, Taylor JM , Davison AS et al. Untargeted metabolomics of COVID-19 patient serum reveals potential prognostic markers of both severity and outcome DOI10.1101/2020.12.09.20246389.
]. Ratio of plasma (or serum) Kyn to Trp levels is used for clinical assessment of the activity of Trp conversion into Kyn. However, Kyn/Trp ratio does not differentiate between stress- (TDO) or inflammation-induced (IDO) activation of Trp conversion into Kyn. Notably, IFNG, concurrently with IDO, induces guanosine triphosphate cyclohydrolase 1, a rate-limiting enzyme of biosynthesis of tetrahydrobiopterin, a cofactor of nitric oxide synthase (Fig. 2) [
Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated medical and psychiatric disorders (review).
]. Therefore, evaluation of plasma/serum levels of neopterin, a stable pteridine derivate, helps to differentiate whether stress (TDO) or inflammation (IDO) is responsible for elevated Kyn/Trp ratio [
Badawy A A-B, Gilles Guillemin. The plasma [kynurenine]/[tryptophan] ratio and indoleamine 2,3- dioxygenase: time for appraisal. Int J Tryptophan Res. 2019;12:1178646919868978.
]. Concurrent elevation of plasma Kyn/Trp ratio and plasma neopterin strongly suggests IDO (rather than TDO)-dependent activation of Trp conversion into Kyn [
Indeed, serum and plasma Trp levels were lower while Kyn and neopterin levels were higher in SARS-CoV-2 –positive than in SARS-CoV-2 –negative subjects [
Thomas T, et al. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight, 2020;23;5(14):e140327. doi: 10.1172/jci.insight.140327.
Lawler N, Gray N, Kimhofer T, Boughton B et al 2021 Systemic perturbations in amine and kynurenine metabolism assicoated with Acute SARS-CoV-2 infection and inflammatory cytokines responses. J Proteome, pre-print.
Lawler N, Gray N, Kimhofer T, Boughton B et al 2021 Systemic perturbations in amine and kynurenine metabolism assicoated with Acute SARS-CoV-2 infection and inflammatory cytokines responses. J Proteome, pre-print.
Roberts I, Muelas MW, Taylor JM , Davison AS et al. Untargeted metabolomics of COVID-19 patient serum reveals potential prognostic markers of both severity and outcome DOI10.1101/2020.12.09.20246389.
Thomas T, et al. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight, 2020;23;5(14):e140327. doi: 10.1172/jci.insight.140327.
Lawler N, Gray N, Kimhofer T, Boughton B et al 2021 Systemic perturbations in amine and kynurenine metabolism assicoated with Acute SARS-CoV-2 infection and inflammatory cytokines responses. J Proteome, pre-print.
O'Farrell K, E. Lim, G. J. Guillemin, A. Harkin. A role for glial-associated kynurenine pathway activation in modulating neuronal outgrowth and complexity Eur Neuropsychopharmacol 2015:S206-7 doi 10.1016/S0924-977X(15)30211-X.
Roberts I, Muelas MW, Taylor JM , Davison AS et al. Untargeted metabolomics of COVID-19 patient serum reveals potential prognostic markers of both severity and outcome DOI10.1101/2020.12.09.20246389.
Data on AA blood levels in COVID-19 patients are controversial. Comparison of COVID-19 patients with control subjects revealed decreased serum AA levels in COVID-19 patients in difference with the elevated levels of all other studied Kyn [
Thomas T, et al. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight, 2020;23;5(14):e140327. doi: 10.1172/jci.insight.140327.
]. Authors suggested that presence of another molecule with the same neutral monoisotopic mass as AA (that, indeed, was decreased in COVID-19 patients) might explain the discrepancy of their results with above cited study. Elevated AA levels correlated with interleukin-18, an IFNG inducing factor. Authors found that elevation of plasma AA (but not other studied Kyn derivatives) was the best negative prognostic marker for unfavorable course of disease (e.g., transfer to ICU, mechanical ventilation, death) in COVID-19 patients. The discovery of elevated AA plasma levels in prospective study of COVID-19 patients [
The role of anthranilic acid in the increase of depressive symptoms and major depressive disorder during treatment for hepatitis C with pegylated interferon-alpha2a and oral ribavirin.
Major psychiatric conditions associated with dysregulations of kynurenine metabolism in non-COVID-19 patients
Review of available data revealed upregulated formation of Kyn, 3HK, KYNA, and, probably, AA in COVID-19 patients. These biochemical changes are known to contribute to mechanism(s) of schizophrenia, depression and anxiety in non-COVID-19 patients.
Schizophrenia. Up-regulated KYNA formation is considered to be causatively linked with major psychopathology in schizophrenia [
]. “KYNA hypothesis” of schizophrenia suggests causative link between major psychopathology of schizophrenia and up-regulated formation of KYNA, an antagonist to NMDA receptors (NMDAR), [
Dabrowski W, Kwiecien JM, Rola R, Klapec M, Stanisz GJ, et al. (2015) Prolonged subdural infusion of kynurenic acid is associated with dose-dependent myelin damage in the rat spinal cord. PLoS One 10:e0142598.
Oxenkrug G, van der Hart M, Roeser J, Summergrad P. Anthranilic acid: A potential biomarker and treatment target for Schizophrenia. Ann Psychiatry Ment Health 2016;4(2):1059-1062. pii: 1059. PMID: 27042691.
Anxiety. Plasma Kyn level and Kyn:Trp ratios were elevated and correlated with severity of anxiety in patients suffered from anxiety, in caffeine-induced anxiety in healthy volunteers and in pregnant women at the end of term, and early puerperium, in comparison with respective controls [
Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system.
], although anxiety and psychoses have observed as well. Positive correlation of Kyn/Trp ratio and neopterin levels with the severity of depression symptoms [
Comai S, Luisa Cavalletto, Liliana Chemello, Elisabetta Bernardinello, et al. Effects of PEG-interferon alpha plus ribavirin on tryptophan metabolism in patients with chronic hepatitis C. Pharmacol Res 2011;63(1):85-92. doi: 10.1016/j.phrs.2010.10.009.
Oxenkrug G. Serotonin-kynurenine hypothesis of depression: historical overview and recent developments. Curr Drug Targets 2013;14(5):514-21. PMID:23514379.
The recent prospective study found elevation of plasma AA as predictor of increased risk of major depressive disorder in interferon-treated hepatitis C virus patients [
The role of anthranilic acid in the increase of depressive symptoms and major depressive disorder during treatment for hepatitis C with pegylated interferon-alpha2a and oral ribavirin.
In addition to IDO-induced depletion of brain serotonin, IDO-induced imbalance between neurotoxic and neuroprotective metabolites was suggested to contribute to development of depression, probably via its effects on glutamatergic neurotransmission [
]. Notably, AA may modulate activity of NMDAR by affecting the balance between antagonists, e.g., KYNA, and agonists, e.g., D-serine (D-amino acid), considering that a single dose of one of DAAO inhibitors, benzoate, robustly elevates plasma AA levels in healthy volunteers [
Subramanian V, Vaidyanathan CS. Anthranilate hydroxylase from Aspergillus niger: new type of NADPH-linked nonheme iron monooxygenase. J Bacteriol. 1984;160(2):651–5. PMCID: PMC214784.
], over-activation of Trp – Kyn pathway (via IFNG – IDO induction) contributes to development of depression, anxiety and psychoses in COVID-19 patients. Therefore, activity of IDO that catalyzes formation of Kyn from Trp; and KMO, KAT and kynase that catalyze Kyn conversion into 3HK, KYNA and AA (respectively) are the most plausible targets for prevention/treatment of psychiatric conditions associated with SARS-CoV- 2 infection. However, inhibition of IFNG and IDO are not suitable targets because such intervention might severely impair immunological defense mechanisms against viral infection [
Kloppenburg M, Verweij CL, Miltenburg AM, Verhoeven AJ, et al. The influence of tetracyclines on T cell activation. Clin Exp Immunol. 1995;102(3):635–41. doi: 10.1111/j.1365-2249.1995.tb03864.x.
]. Inhibition of KAT and Kynase might be a preferable intervention. Notably, benserazide and carbidopa that already used in treatment of Parkinson’s disorder, inhibit Kynase and KAT in in vitro model [
Benserazide, an inhibitor of peripheral kynurenine metabolism, attenuates olanzapine-induced weight gain, insulin resistance, and dyslipidemia in C57Bl/6j mice.
]. Future studies might explore the effect of benserazide and other inhibitors of down-stream Kyn metabolism on psychiatric conditions associated with SARS-CoV-2 infection.
Trp – Kyn pathway metabolites as biological markers of psychiatric conditions associated with SARS-CoV-2 infection
Association of Trp – Kyn pathway dysregulation with psychiatric diseases and elevated levels of Kyn, KYNA and AA in COVID-19 patients suggest that assessment of these metabolites might be used to identify COVID- 19 patients at risk for development of psychiatric condition. Notably, Kyn and AA penetrate brain-blood barrier, and, therefore, their blood levels is expected to correlate with their brain levels [
]. On the other hand, it is reasonably to suggest that SARS-CoV-2 infection-induced overactivation of Trp – Kyn pathway is a systemic effect, not limited just to peripheral Kyn metabolism. Therefore, evaluation of plasma/serum levels of Kyn metabolites might be explored as biological markers for prediction of the risk of psychiatric complication in COVID-19 patients. Notably, polymorphism of IFNG (+874) T/A (rs2430561) gene affects the amount of IFNG protein produced in response to viral infection, and might identify patients at risk for psychiatric side effects. We previously reported that carriers of T (high producer) allele were more frequent among depressed than non-depressed IFN-alpha-treated hepatitis C patients [
]. There was no association of not functional IFNG polymorphisms (rs3824259; rs10089084 and rs35099072) with IFN-α-induced depression in hepatitis C virus patient [
], it might be importance to explore the effect of polymorphism of IFNG and other genes impacting production of key enzymes of Trp – Kyn pathway on risk of psychiatric sideeffects in COVID-19 patients. Development of markers usable for personalized psychiatry has to consider several already known factors affecting Trp – Kyn pathway such as gender and aging. Thus, IDO activation (increased Kyn:Trp ratio) was more prominent (and positively correlated with age) in males than females SARS-CoV2- positive patients [
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Paul Summergrad Consultant: Mental Health Data Services, Inc. Compass Pathways Ltd., Pear Therapeutics, Cowen Stock or Stock Options: Mental Health Data Services, Inc. Quartet Health, Inc., Pear Therapeutics, Karuna Therapeutics, ATAI, Cybin. Gregory Oxenkrug has nothing to declare.
References
Varatharaj A, Thomas N, Ellul MA, Davies, N.W.S., et al. (2020 June 25). Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry. S2215-0366(20)30287-X. doi: 10.1016/S2215-0366(20)30287-X.
Baranyi A, Meinitzer A, Breitenecker RJ, Amouzadeh-Ghadikolai O, et al Quinolinic Acid Responses during Interferon-alpha-Induced Depressive Symptomatology in Patients with Chronic Hepatitis C Infection - A Novel Aspect for Depression and Inflammatory Hypothesis. PLoS One 2015;10(9):e0137022. doi: 10.1371/journal.pone.0137022. eCollection 2015.PMID: 26368809.
Roberts I, Muelas MW, Taylor JM , Davison AS et al. Untargeted metabolomics of COVID-19 patient serum reveals potential prognostic markers of both severity and outcome DOI10.1101/2020.12.09.20246389.
Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated medical and psychiatric disorders (review).
Badawy A A-B, Gilles Guillemin. The plasma [kynurenine]/[tryptophan] ratio and indoleamine 2,3- dioxygenase: time for appraisal. Int J Tryptophan Res. 2019;12:1178646919868978.
Thomas T, et al. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight, 2020;23;5(14):e140327. doi: 10.1172/jci.insight.140327.
Lawler N, Gray N, Kimhofer T, Boughton B et al 2021 Systemic perturbations in amine and kynurenine metabolism assicoated with Acute SARS-CoV-2 infection and inflammatory cytokines responses. J Proteome, pre-print.
O'Farrell K, E. Lim, G. J. Guillemin, A. Harkin. A role for glial-associated kynurenine pathway activation in modulating neuronal outgrowth and complexity Eur Neuropsychopharmacol 2015:S206-7 doi 10.1016/S0924-977X(15)30211-X.
The role of anthranilic acid in the increase of depressive symptoms and major depressive disorder during treatment for hepatitis C with pegylated interferon-alpha2a and oral ribavirin.
Dabrowski W, Kwiecien JM, Rola R, Klapec M, Stanisz GJ, et al. (2015) Prolonged subdural infusion of kynurenic acid is associated with dose-dependent myelin damage in the rat spinal cord. PLoS One 10:e0142598.
Oxenkrug G, van der Hart M, Roeser J, Summergrad P. Anthranilic acid: A potential biomarker and treatment target for Schizophrenia. Ann Psychiatry Ment Health 2016;4(2):1059-1062. pii: 1059. PMID: 27042691.
Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system.
Comai S, Luisa Cavalletto, Liliana Chemello, Elisabetta Bernardinello, et al. Effects of PEG-interferon alpha plus ribavirin on tryptophan metabolism in patients with chronic hepatitis C. Pharmacol Res 2011;63(1):85-92. doi: 10.1016/j.phrs.2010.10.009.
Oxenkrug G. Serotonin-kynurenine hypothesis of depression: historical overview and recent developments. Curr Drug Targets 2013;14(5):514-21. PMID:23514379.
Subramanian V, Vaidyanathan CS. Anthranilate hydroxylase from Aspergillus niger: new type of NADPH-linked nonheme iron monooxygenase. J Bacteriol. 1984;160(2):651–5. PMCID: PMC214784.
Kloppenburg M, Verweij CL, Miltenburg AM, Verhoeven AJ, et al. The influence of tetracyclines on T cell activation. Clin Exp Immunol. 1995;102(3):635–41. doi: 10.1111/j.1365-2249.1995.tb03864.x.
Benserazide, an inhibitor of peripheral kynurenine metabolism, attenuates olanzapine-induced weight gain, insulin resistance, and dyslipidemia in C57Bl/6j mice.
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