Significance of Catecholamine Biosynthetic/Metabolic Pathway in SARS-CoV-2 Infection and COVID-19 Severity

Abstract

The SARS-CoV-2 infection was previously associated with the expression of the dopamine biosynthetic enzyme L-Dopa decarboxylase (DDC). Specifically, a negative correlation was detected between DDC mRNA and SARS-CoV-2 RNA levels in in vitro infected epithelial cells and the nasopharyngeal tissue of COVID-19 patients with mild/no symptoms. However, DDC, among other genes related to both DDC expression and SARS-CoV-2-infection (ACE2, dACE2, EPO), was upregulated in these patients, possibly attributed to an orchestrated host antiviral response. Herein, by comparing DDC expression in the nasopharyngeal swab samples of severe/critical to mild COVID-19 cases, we showed a 20 mean-fold reduction, highlighting the importance of the expression of this gene as a potential marker of COVID-19 severity. Moreover, we identified an association of SARS-CoV-2 infection with the expression of key catecholamine biosynthesis/metabolism-related genes, in whole blood samples from hospitalized patients and in cultured cells. Specifically, viral infection downregulated the biosynthetic part of the dopamine pathway (reduction in DDC expression up to 7.5 mean-fold), while enhanced the catabolizing part (increase in monoamine oxidases A and B expression up to 15 and 10 mean-fold, respectively) in vivo, irrespectively of the presence of comorbidities. In accordance, dopamine levels in the sera of severe cases were reduced (up to 3.8 mean-fold). Additionally, a moderate positive correlation between DDC and MAOA mRNA levels (r = 0.527, p < 00001) in the blood was identified upon SARS-CoV-2-infection. These observations were consistent to the gene expression data from SARS-CoV-2-infected Vero E6 and A549 epithelial cells. Furthermore, L-Dopa or dopamine treatment of infected cells attenuated the virus-derived cytopathic effect by 55% and 59%, respectively. The SARS-CoV-2 mediated suppression of dopamine biosynthesis in cell culture was, at least in part, attributed to hypoxia-like conditions triggered by viral infection. These findings suggest that L-Dopa/dopamine intake may have a preventive or therapeutic value for COVID-19 patients.

Uncovering the Effect of SARS-CoV-2 on Liver Metabolism via Genome-Scale Metabolic Modeling for Reprogramming and Therapeutic Strategies

“…Several studies in the literature demonstrated that the supplements used in this study like dopamine, glucosamine, D -xylose, cysteine, ( R )-3-hydroxybutanoate, lovastatin, and simvastatin have the potential to develop therapeutic strategies to fight SARS-CoV-2. 50 − 62 Dopamine is an important neurotransmitter and required for proper functioning of the body including movement, memory, and motivation. Administration of dopamine reduced the viral replication in CaLu-3 human lung epithelial cells and virus-based cytopathic effect in Vero E6 epithelial cells infected with SARS-CoV-2.…”

“…Administration of dopamine reduced the viral replication in CaLu-3 human lung epithelial cells and virus-based cytopathic effect in Vero E6 epithelial cells infected with SARS-CoV-2. 50 , 51 Glucosamine is a common dietary supplement that promotes joint health. Its administration to infected Calu-3 cells and mice inhibited SARS-CoV-2 replication in vitro and in vivo , respectively.…”

Integrated UPLC-MS, network pharmacology, and intestinal flora analysis to determine the treatment effect of Qiangzhi decoction on comorbid Tourette syndrome and RRTI

“…Another study showed that dopamine could be synthesized and stored in follicular helper T cells and released upon cognate interaction with B cells ( 41 ). In a study of SARS-CoV-2 infected patients, dopamine biosynthetic enzyme L-Dopa decarboxylase mRNA expression was found to be negatively correlated with SARS-CoV-2 RNA levels, and viral infection downregulated the biosynthetic portion of the dopamine pathway regardless of comorbidities ( 42 ).…”

Virus infection participates in the occurrence and development of human diseases through monoamine oxidase

“…26,69,70 Mpekoulis et al found that SARS-CoV-2 infection is associated with the biosynthesis and metabolism of CAs. 27 SARS-CoV-2 induces hypoxia-like conditions in cells, downregulates DDC, upregulates MAOA and MAOB, and reduces CA levels, thereby facilitating selfreplication. 27 Cuperlovic-Culf et al have investigated the role of MAO activity in SARS-CoV-2 infection and delirium.…”

“…27 SARS-CoV-2 induces hypoxia-like conditions in cells, downregulates DDC, upregulates MAOA and MAOB, and reduces CA levels, thereby facilitating selfreplication. 27 Cuperlovic-Culf et al have investigated the role of MAO activity in SARS-CoV-2 infection and delirium. 28 Their analysis of published metabonomic data from patients with COVID-19…”