Interferon-gamma Mediated Metabolic Pathways in Hospitalized Patients During Acute and Reconvalescent COVID-19

Abstract

Background: Fatigue, sleep disturbance, and neurological symptoms during and after COVID-19 are common and might be associated with inflammation-induced changes in tryptophan (Trp) and phenylalanine (Phe) metabolism.

Aim: This pilot study investigated interferon gamma inducible biochemical pathways (namely Trp catabolism, neopterin, tyrosine [Tyr], and nitrite formation) during acute COVID-19 and reconvalescence.

Patients and methods: Thirty one patients with moderate to severe COVID-19 admitted to the University Hospital of Innsbruck in early 2020 (March-May) were followed up. Neurotransmitter precursors Trp, Phe, Tyr as well as kynurenine (Kyn), neopterin, nitrite, and routine laboratory parameters were analyzed during acute infection and at a follow-up (FU) 60 days thereafter. Clinical symptoms of patients (neurological symptoms, fatigue, sleep disturbance) were recorded and associations with concentrations of laboratory parameters investigated.

Results and conclusion: Almost half of the patients suffered from neurological symptoms (48.4%), the majority of patients experienced sleep difficulties (56.7%) during acute COVID-19. Fatigue was present in nearly all patients. C-reactive protein (CRP), interleukin-6 (IL-6), neopterin, Kyn, Phe concentrations were significantly increased, and Trp levels depleted during acute COVID-19. Patients with sleep impairment and neurological symptoms during acute illness presented with increased CRP and IL-6 concentrations, Trp levels were lower in patients with sleep disturbance. In general, inflammatory markers declined during reconvalescence. A high percentage of patients suffered from persistent symptoms at FU (neurological symptoms: 17.2%, fatigue: 51.7%, sleeping disturbance: 34.5%) and had higher CRP concentrations. Nitrite and Phe levels were lower in patients with sleeping difficulties at FU and Kyn/Trp ratio, as indicator of IDO activity, was significantly lower in patients with neurological symptoms compared to patients without them at FU. In summary, inflammation induced alterations of amino acid metabolism might be related to acute and persisting symptoms of COVID-19.

Keywords: COVID-19; IDO; Long Covid; interferon-gamma; neopterin; phenylalanine; tryptophan.

Figure 1.

Interferon gamma (IFN-γ)-dependent and related biochemical pathways. Inflammatory cascades stimulate immunobiochemical pathways, with IFN-γ being the main activating cytokine of neopterin formation via GTP cyclohydrolase 1 (GTP-CH-I) and tryptophan (Trp) catabolism along the kynurenine (Kyn) axis via indoleamine 2,3-dioxygenase 1 (IDO-1) in human macrophages (MΦ) and dendritic cells (DC). The shift toward neopterin production runs at the expense of tetrahydrobiopterin (BH4) in these cell types. BH4 is crucial for the functioning of several monoxygenases, for example phenylalanine 4-monooxygenase (PAH), tyrosine 3-monooxygenase (TH), tryptophan 5-monooxygenases (TPH), and nitric oxide synthases (NOS). Though BH4 is synthetized by other cell types, too, it is oxidation labile and availabilities may become limiting. In addition, a prooxidative milieu leads to dysbalances in the Kyn downstream axis, leading to immunological and neurological consequences. Abbreviations: KynA, kynurenic acid; NAD, nicotinamide adenine dinucleotide; NK, neutral killer cells; NO, nitric oxide; NOX, NADPH oxidase; Phe, phenylalanine; Arg, arginine; QuinA, quinolinic acid; ROS, reactive oxygen species; Tyr, tyrosine. Metabolites analyzed in this study are in bold and highlighted in orange. Enzymes are shown in blue and amino acids in red text.

Figure 2.

Flow chart.

Figure 3.

CRP, IL-6, and Trp serum concentrations during acute COVID-19 sex-stratified for sleep disturbance during acute COVID-19.

Figure 4.

Relationship between neopterin levels during acute COVID-19 and Kyn/Trp and Phe/Tyr during acute illness respectively, with corresponding results yielded by Spearman Rank Test.

Figure 5.

CRP concentrations 60 days after acute COVID-19 (FU) sex-stratified for fatigue.

Figure 6.

Nitrite, CRP, and Phe concentrations at FU sex-stratified for sleep disturbance at FU.

Figure 7.

Neopterin and Kyn/Trp at FU respectively sex-stratified for neurological symptoms at FU.