key: cord-0810289-fp8g173y
authors: Oxenkrug, Gregory; Summergrad, Paul
title: Peripheral Kynurenines as Biomarkers and Targets for Prevention and Treatment of Psychiatric Conditions associated with SARS-CoV-2 infection
date: 2021-09-24
journal: Personalized Medicine in Psychiatry
DOI: 10.1016/j.pmip.2021.100088
sha: bc0a970448786cd75844fc324ac5d58ed28ee19e
doc_id: 810289
cord_uid: fp8g173y

Present review focuses on the possible role of tryptophan (Trp) – kynurenine (Kyn) pathwayin 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

Accumulating evidences pointed out to emergence of severe psychiatric conditions in coronavirus disease 2019 patients [1] . Proposed mechanism(s) of such complications did not include dysregulation of Trp -Kyn pathway [2] despite the data on SARS-CoV-2 infection-induced overproduction of IFNG [3] , an inducer of key enzymes of Trp -Kyn pathway [4] , and association of IFNG-inducible upregulation 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 [5] 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 (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 [6] (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.

[2]. 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) [ Abbreviations: Trp -tryptophan; Kyn -kynurenine; KYNA -kynurenic acid; 3HK -3-hydroxykynurenine; XA -xanthurenic acid; AA -anthranilic acid; 3HAA -3-hydroxyanthranilic acid; QIUN -quinolinic acid; BH4 -tetrahydrobiopterin; NO -nitric oxide; NAD+ -nicotinamide adenine dinucleotide; TDO/IDOtryptophan/indoleamine-2,3-dioxygenases; KMO -kynurenine 3-monooxygenase; Kynase -kynureninase; KAT -kynurenine aminotransferases; 3HAO -3-hydroxyanthranilate 3,4-dioxygenase

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 3monooxygenase (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 [7, 8] .

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) [9, 10] .

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 [11] .

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 [12] . 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) [13]. 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 [14] . Concurrent elevation of plasma Kyn/Trp ratio and plasma neopterin strongly suggests IDO (rather than TDO)-dependent activation of Trp conversion into Kyn [15] .

Abbreviations: IFNG -interferon gamma; Kyn -kynurenine; NAD+ -nicotinamide adenine dinucleotide; BH2 -7,8-dihydroneopterin; NO -nitric oxide; IDO -indoleamine-2,3-dioxygenase 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 [16] [17] [18] . Kyn/Trp ratios and neopterin levels correlated with serum IFNG levels and severity of infection, and predicted poor outcome of COVID-19 disease [17, 18] . Overactivation of Trp conversion into Kyn was suggested as the top pathway affected in COVID-19 patients [12] .

Blood levels of KYNA and 3HK were higher in SARS-CoV-2 positive in comparison with SARS-CoV-2 negative subjects [16, 17, 19] , most likely because of increased Kyn levels (due to IFNG-induced IDO activation) and KMO activation by IFNG [20] . The increase of plasma KYNA levels was over 2-fold in severe cases and in patients who died [12] .

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 [16] . Prospective study, on contrary, found elevated plasma AA levels in patients hospitalized in standard conditions (not at Intensive Care Unit) [19] . 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 [19] is in line with finding of elevated plasma AA levels in prospective study of hepatitis C patients treated with interferon-alpha [21] . Notably, IFNG activates kynase, the enzyme that catalyzes AA formation from Kyn [22].

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 [23] . "KYNA hypothesis" of schizophrenia suggests causative link between major psychopathology of schizophrenia and up-regulated formation of KYNA, an antagonist to NMDA receptors (NMDAR), [24] and a ligand to aryl hydrocarbon and GPR35 receptors [25] . KYNA hypothesis is supported by findings of elevated KYNA concentrations in brains [23] and CSF [26] of schizophrenia patients, and of KYNAinduced schizophrenia-associated disruption of pre-pulse inhibition [27] , impairment of cognitive functions [28 ] , damage of spinal cord myelin [29 ] and impairment of oligodendrocyte viability in animal experiments [30] .

AA levels were elevated in plasma and serum of schizophrenia patients [11, 31] . 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 [32] . Further studies corroborated association of anxiety with dysregulation of Trp -Kyn pathway [33] .

Depression is the most frequent (up to 50%) psychiatric complication of interferon-alpha treatment of hepatitis C virus (HCV) [34] and melanoma patients [35] , although anxiety and psychoses have observed as well. Positive correlation of Kyn/Trp ratio and neopterin levels with the severity of depression symptoms [36] , and decreased content of plasma and blood platelets serotonin [37] suggests that IDO-induced shift of Trp from methoxyindole to Kyn pathways contributes to development of depression in interferon treated [38] [39] [40] .

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 [21] . AA plasma levels were associated with severity of depression symptoms in female patients with no clinical and biochemical signs of inflammation [41] .

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 [9] . 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 [42] , and that AA (aka, 2-aminobenzoic acid) may be deaminated in vivo into benzoate [43] .

Present review suggests that in addition to factors that were considered as contributing to development of COVID-associated psychiatric conditions [2], 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 [44] [45] [46] . 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 [47] . We found that sub-chronic administration of benserazide to C57/Bl/j6 mice attenuated olanzapine-induced development of metabolic syndrome [48] apparently associated with up-regulated formation of AA and XA [49] . 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.

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 [50] . 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 nondepressed IFN-alpha-treated hepatitis C patients [52] . There was no association of not functional IFNG polymorphisms (rs3824259; rs10089084 and rs35099072) with IFN-α-induced depression in hepatitis C virus patient [53] . Considering that IFNG activates kynase, that catalyzes formation of AA, a presumed negative predictor of COVID-19 outcome [19] , 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 [18] .

PostolacheTT and Benros ME. Targetable biological mechanisms implicated in emergent psychiatric conditions associated with SRAS-CoV-2 infection

Immune determinants of COVID-19 disease: presentation and severity

Induction of indoleamine dioxygenase by interferon in mice: A study with different recombinant interferons and various cytokines Biochemical and Biophysical Research Communications

Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactionsImmunity

Kynurenines in the mammalian brain: When physiology meets pathology

Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites

Role of Kynurenine Metabolism Pathway Activation in Major Depressive Disorders

Quinolinic Acid Responses during Interferon-alpha-Induced Depressive Symptomatology in Patients with Chronic Hepatitis C Infection -A Novel Aspect for Depression and Inflammatory Hypothesis

Xanthurenic Acid Activates mGlu2/3 Metabotropic Glutamate Receptors and is a Potential Trait Marker for

Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated medical and psychiatric disorders (review)

3-Dioxygenase: Time for

Serum neopterin levels in relation to mild and severe COVID-19

COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status

Systemic perturbations in amine and kynurenine metabolism assicoated with Acute SARS-CoV-2 infection and inflammatory cytokines responses

A role for glial-associated kynurenine pathway activation in modulating neuronal outgrowth and complexity

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

Increased cortical kynurenate in in schizophrenia

The kynurenic acid hypothesis of schizophrenia

AhR and IDO1 in pathogenesis of Covid-19 and the "Systemic AhR Activation Syndrome:" a translational review and therapeutic perspectives

Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia

Endogenous kynurenic acid disrupts prepulse inhibition

Elevations of endogenous kynurenic acid produce spatial working memory deficits

Prolonged subdural infusion of kynurenic acid is associated with dose-dependent myelin damage in the rat spinal cord

Kynurenic Acid Induces Impairment of Oligodendrocyte Viability: On the Role of Glutamatergic Mechanisms

Lynurenine in blood plasma and DST inpatients with endogenous anxiety and depression

Neuroinflammation and the Immune-Kynurenine Pathway in

Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system

Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy

Elisabetta Bernardinello, et al Effects of PEG-interferon alpha plus ribavirin on tryptophan metabolism in patients with chronic hepatitis C

Platelet serotonin (5-HT) levels in interferon-treated patients with hepatitis C and its possible association with interferon-induced depression

GF: Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect

Serotonin-kynurenine hypothesis of depression: historical overview and recent developments

Role of the kynurenine metabolism pathway in inflammation-induced depression -Preclinical approaches Curr Top Behav Neurosci

Plasma anthranilic acid and leptin levels predict HAM-D scores in depressed women

Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans

Anthranilate hydroxylase from Aspergillus niger: new type of NADPH-linked nonheme iron monooxygenase

Effects of benserazide on tryptophan metabolism in the mouse

Benserazide, an Inhibitor of Peripheral Kynurenine Metabolism, Attenuates Olanzapine-Induced Weight Gain, Insulin Resistance, and Dyslipidemia in C57Bl/6j Mice

Kynurenic acid, an aryl hydrocarbon receptor ligand, is elevated in serum of Zucker fatty rats

Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism

Interferon-gamma (+874) T/A genotypes and risk of IFN-alpha-induced depression

Lack of association of indoleamine 2,3 -dioxygenase polymorphisms with interferon-alpha -related depression inHepatis C