Alteration of L-Dopa decarboxylase expression in SARS-CoV-2 infection and its association with the interferon-inducible ACE2 isoform

Abstract

L-Dopa decarboxylase (DDC) is the most significantly co-expressed gene with ACE2, which encodes for the SARS-CoV-2 receptor angiotensin-converting enzyme 2 and the interferon-inducible truncated isoform dACE2. Our group previously showed the importance of DDC in viral infections. We hereby aimed to investigate DDC expression in COVID-19 patients and cultured SARS-CoV-2-infected cells, also in association with ACE2 and dACE2. We concurrently evaluated the expression of the viral infection- and interferon-stimulated gene ISG56 and the immune-modulatory, hypoxia-regulated gene EPO. Viral load and mRNA levels of DDC, ACE2, dACE2, ISG56 and EPO were quantified by RT-qPCR in nasopharyngeal swab samples from COVID-19 patients, showing no or mild symptoms, and from non-infected individuals. Samples from influenza-infected patients were analyzed in comparison. SARS-CoV-2-mediated effects in host gene expression were validated in cultured virus-permissive epithelial cells. We found substantially higher gene expression of DDC in COVID-19 patients (7.6-fold; p = 1.2e-13) but not in influenza-infected ones, compared to non-infected subjects. dACE2 was more elevated (2.9-fold; p = 1.02e-16) than ACE2 (1.7-fold; p = 0.0005) in SARS-CoV-2-infected individuals. ISG56 (2.5-fold; p = 3.01e-6) and EPO (2.6-fold; p = 2.1e-13) were also increased. Detected differences were not attributed to enrichment of specific cell populations in nasopharyngeal tissue. While SARS-CoV-2 virus load was positively associated with ACE2 expression (r≥0.8, p<0.001), it negatively correlated with DDC, dACE2 (r≤−0.7, p<0.001) and EPO (r≤−0.5, p<0.05). Moreover, a statistically significant correlation between DDC and dACE2 expression was observed in nasopharyngeal swab and whole blood samples of both COVID-19 and non-infected individuals (r≥0.7). In VeroE6 cells, SARS-CoV-2 negatively affected DDC, ACE2, dACE2 and EPO mRNA levels, and induced cell death, while ISG56 was enhanced at early hours post-infection. Thus, the regulation of DDC, dACE2 and EPO expression in the SARS-CoV-2-infected nasopharyngeal tissue is possibly related with an orchestrated antiviral response of the infected host as the virus suppresses these genes to favor its propagation.

Association of Hepatitis C Virus Replication with the Catecholamine Biosynthetic Pathway

“…Little is known about the association of the monoamine biosynthetic and metabolic pathway with viral infections. In addition to our previous reports on the association of DDC with HCV [7] and SARS-CoV-2 [37] infections, there is a study supporting increases of MAO-B transcription upon Simian immunodeficiency virus infection in macaque brain [38]. Moreover, Rotavirus (RV) and Dengue virus (DENV) have been shown to stimulate 5-HT release from the host cells [39,40].…”

Impact of Age and Sex on Antibody Response Following the Second Dose of COVID-19 BNT162b2 mRNA Vaccine in Greek Healthcare Workers

“…Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a pathogen in December 2019 and is responsible for coronavirus disease 2019 (COVID- 19) [1]. This novel virus causes symptoms that range from fever, dry cough, and dyspnea to the development of acute pneumonia, while neurological complications have also been reported [2], including damage in the dopaminergic system [3,4]. SARS-CoV-2-infection can be fatal for patients with underlying conditions regardless of their age, while healthy individuals that are treated can recover within 2-4 weeks [5].…”

Dengue Virus Replication Is Associated with Catecholamine Biosynthesis and Metabolism in Hepatocytes

“…The relationship between catecholamine biosynthesis/metabolism and viral replication is not restricted to Flaviviridae family [ 33 , 86 ] as the pathogenesis of several viruses has been related to this pathway [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. Our previous work on SARS-CoV-2, another single-stranded RNA virus, has revealed a significant correlation between DDC expression and viral infection in both nasopharyngeal swab samples of COVID-19 patients and infected cultured airway epithelial cells [ 34 ]. SARS-CoV-2 was suggested to suppress DDC to favor its propagation.…”

“…Limited data exist linking viral infections with monoamine biosynthesis and metabolism apart from our previously reported findings on the association of DDC with the infections by HCV and DV [ 21 , 33 ] and SARS-CoV-2 [ 34 ]. Increased transcription of MAO-B upon infection by Simian immunodeficiency virus [ 35 ] and stimulation of 5-HT release from the host cells by Rotavirus [ 36 ] and DV [ 37 ] have been shown; moreover, elevation of NE and EPI plasma levels in patients with neurological complications after Enterovirus 71 (EV71) infection with a parallel enhancement of virus titers and infectivity in human leukocyte cell lines by the two catecholamines [ 38 ] has been observed.…”