Anxiety due to Long COVID is partially driven by activation of the tryptophan catabolite (TRYCAT) pathway

Al‐Hakeim, Hussein Kadhem; Abed, Anwar Khairi; Almulla, Abbas F.; Moustafa, Shatha Rouf; Maes, Michaël

doi:10.1016/j.ajp.2023.103723

Cited by 12 publications

(4 citation statements)

References 12 publications

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“…In COVID-19 patients, other authors observed increased activity of the TRYCAT pathway 60 , 61 , as manifested by decreased tryptophan concentration and increased levels of KN and NFK, resulting from increased IDO activity under the influence of pro-inflammatory cytokines. In addition, the SARS-CoV-2 virus stimulates the aryl hydrocarbon receptor (AhR) and increases KN levels, which leads to the systemic AhR activation syndrome (SAAR) that intensifies inflammation, induces thrombophilia, and contributes to organ damage 62 , 63 .…”

Section: Discussionmentioning

confidence: 94%

Significance of nitrosative stress and glycoxidation products in the diagnosis of COVID-19

Wolszczak-Biedrzycka,

Dorf,

Matowicka-Karna

et al. 2024

Sci Rep

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Nitrosative stress promotes protein glycoxidation, and both processes can occur during an infection with the SARS-CoV-2 virus. Therefore, the aim of this study was to assess selected nitrosative stress parameters and protein glycoxidation products in COVID-19 patients and convalescents relative to healthy subjects, including in reference to the severity of COVID-19 symptoms. The diagnostic utility of nitrosative stress and protein glycoxidation biomarkers was also evaluated in COVID-19 patients. The study involved 218 patients with COVID-19, 69 convalescents, and 48 healthy subjects. Nitrosative stress parameters (NO, S-nitrosothiols, nitrotyrosine) and protein glycoxidation products (tryptophan, kynurenine, N-formylkynurenine, dityrosine, AGEs) were measured in the blood plasma or serum with the use of colorimetric/fluorometric methods. The levels of NO (p = 0.0480), S-nitrosothiols (p = 0.0004), nitrotyrosine (p = 0.0175), kynurenine (p < 0.0001), N-formylkynurenine (p < 0.0001), dityrosine (p < 0.0001), and AGEs (p < 0.0001) were significantly higher, whereas tryptophan fluorescence was significantly (p < 0.0001) lower in COVID-19 patients than in the control group. Significant differences in the analyzed parameters were observed in different stages of COVID-19. In turn, the concentrations of kynurenine (p < 0.0001), N-formylkynurenine (p < 0.0001), dityrosine (p < 0.0001), and AGEs (p < 0.0001) were significantly higher, whereas tryptophan levels were significantly (p < 0.0001) lower in convalescents than in healthy controls. The ROC analysis revealed that protein glycoxidation products can be useful for diagnosing infections with the SARS-CoV-2 virus because they differentiate COVID-19 patients (KN: sensitivity—91.20%, specificity—92.00%; NFK: sensitivity—92.37%, specificity—92.00%; AGEs: sensitivity—99,02%, specificity—100%) and convalescents (KN: sensitivity—82.22%, specificity—84.00%; NFK: sensitivity—82,86%, specificity—86,00%; DT: sensitivity—100%, specificity—100%; AGE: sensitivity—100%, specificity—100%) from healthy subjects with high sensitivity and specificity. Nitrosative stress and protein glycoxidation are intensified both during and after an infection with the SARS-CoV-2 virus. The levels of redox biomarkers fluctuate in different stages of the disease. Circulating biomarkers of nitrosative stress/protein glycoxidation have potential diagnostic utility in both COVID-19 patients and convalescents.

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Section: Discussionmentioning

confidence: 94%

Significance of nitrosative stress and glycoxidation products in the diagnosis of COVID-19

Wolszczak-Biedrzycka,

Dorf,

Matowicka-Karna

et al. 2024

Sci Rep

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“…Patients who died from COVID have increased kynurenine signaling 81 , including increased KYNA in brain 34 . Fluid biomarker data from patients with long-COVID are just beginning to emerge, but recent findings show that plasma kynurenine levels correlate with symptoms of cognitive deficits 5 , as well as depression and anxiety 6,82 , the latter which may be related to decreased dlPFC top-down control of emotion 83 . Interestingly, KYNA can perpetuate kynurenine signaling by activating IDO metabolism of tryptophan 81 , as schematically illustrated in Figure 7f, and this may sustain symptoms even after the initial cytokine inflammatory response is over 84 .…”

Section: Discussionmentioning

confidence: 99%

Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition

Yang,

Datta,

Krienen

et al. 2024

Preprint

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SummaryCognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer’s disease, and have been correlated with kynurenine inflammatory signaling. Kynurenine is further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and α7-nicotinic receptors (nic-α7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may cause higher cognitive deficits in these disorders. The current study found that KYNA and its synthetic enzyme, KAT II, have greatly expanded expression in primate dlPFC in both glia and neurons. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-α7Rs, while inhibition of KAT II enhanced neuronal firing in aged macaques. Systemic administration of agents that reduce KYNA production similarly improved cognitive performance in aged monkeys, suggesting a therapeutic avenue for the treatment of cognitive deficits in neuroinflammatory disorders.

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“…Some of the authors of the present study have discovered molecular pathways that are involved in the development of symptoms in individuals with Long COVID disease. These pathways include the activation of the immune-inflammatory system (IRS), specifically the NLRP3, M1 macrophage, T helper (Th)-1, and Th-17 activation [6][7][8][11][12][13]. Additionally, some of these authors found activation of the compensatory immunoregulatory system, as well as oxidative and nitrosative stress reactions.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, some of these authors found activation of the compensatory immunoregulatory system, as well as oxidative and nitrosative stress reactions. Furthermore, there was an observed increase in insulin resistance, a decrease in tryptophan levels, and an increase in tryptophan catabolites, such as kynurenine [11,12]. A recent meta-analysis has found that Long COVID disease is associated with elevated levels of C-reactive protein (CRP), D-dimers, lactate dehydrogenase, leukocytes, lymphocytes, and interleukin (IL)-6 [14].…”

Section: Introductionmentioning

confidence: 99%

From HHV-6 reactivation to autoimmune reactivity against tight junctions and neuronal antigens, to inflammation, depression, and chronic fatigue syndrome due to Long COVID

Maes,

Almulla,

Tang

et al. 2024

Preprint

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BackgroundInflammation and autoimmune responses contribute to the pathophysiology of Long COVID, and its affective and chronic fatigue syndrome (CFS) symptoms, labeled “the physio-affective phenome.”ObjectivesTo investigate whether Long COVID and its physio-affective phenome are linked to autoimmunity to the tight junction proteins, zonulin and occludin (ZOOC), and immune reactivity to lipopolysaccharides (LPS), and whether the latter are associated with signs of human herpes virus-6 reactivation (HHV-6), autoimmunity directed against oligodendrocyte and neuronal proteins, including myelin basic protein (MBP).MethodsIgA/IgM/IgG responses to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), HHV-6, ZOOC, and neuronal proteins, C-reactive protein (CRP) and advanced oxidation protein products (AOPP), were measured in 90 Long COVID patients and 90 healthy controls. The physio-affective phenome was conceptualized as a factor extracted from physical and affective symptom domains.ResultsNeural network identified IgA directed to LPS (IgA-LPS), IgG-ZOOC, IgG-LPS, and IgA-ZOOC as the most important variables associated with Long COVID diagnosis with an area under the ROC curve of 0.755. Partial Least Squares analysis showed that 40.9% of the variance in the physio-affective phenome was explained by CRP, IgA-MPB and IgG-MBP. A large part of the variances in both autoimmune responses to MBP (36.3-39.7%) was explained by autoimmunity (IgA and IgG) directed to ZOOC. The latter was strongly associated with indicants of HHV-6 reactivation, which in turn was associated with increased IgM-SARS-CoV-2.ConclusionsAutoimmunity against components of the tight junctions and increased bacterial translocation may be involved in the pathophysiology of Long COVID’s physio-affective phenome.

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Anxiety due to Long COVID is partially driven by activation of the tryptophan catabolite (TRYCAT) pathway

Cited by 12 publications

References 12 publications

Significance of nitrosative stress and glycoxidation products in the diagnosis of COVID-19

Significance of nitrosative stress and glycoxidation products in the diagnosis of COVID-19

Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition

From HHV-6 reactivation to autoimmune reactivity against tight junctions and neuronal antigens, to inflammation, depression, and chronic fatigue syndrome due to Long COVID

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